A Review of PARP-1 Inhibitors: Assessing Emerging Prospects and Tailoring Therapeutic Strategies

Abstract

Eukaryotic organisms contain an enzyme family called poly (ADP-ribose) polymerases (PARPs), which is responsible for the poly (ADP-ribosylation) of DNA-binding proteins. PARPs are members of the cell signaling enzyme class. PARP-1, the most common isoform of the PARP family, is responsible for more than 90% of the tasks carried out by the PARP family as a whole. A superfamily consisting of 18 PARPs has been found. In order to synthesize polymers of ADP-ribose (PAR) and nicotinamide, the DNA damage nick monitor PARP-1 requires NAD+ as a substrate. The capability of PARP-1 activation to boost the transcription of proinflammatory genes, its ability to deplete cellular energy pools, which leads to cell malfunction and necrosis, and its involvement as a component in the process of DNA repair are the three consequences of PARP-1 activation that are of particular significance in the process of developing new drugs. As a result, the pharmacological reduction of PARP-1 may result in an increase in the cytotoxicity toward cancer cells.

Key words

PARPs - DNA repair - Synthetic Compounds - Cancer cells

Introduction

Cancer, which is the outcome of the body's uncontrolled cell growth and development, is one of the main causes of mortality on a global scale [1]. Unrestricted proliferation, invasion, and metastasis are characteristics of cancer, which arises as a consequence of a multi-step process leading to the build-up of several genomic alterations [2]. Global cancer burden estimates are provided by the GBD (Global Burden of Diseases) 2019 study, which was updated and enhanced from earlier GBD cycles [3]. These predictions varied significantly by SDI (Sociodemographic Index) quintile, illuminating cancer burden variations around the world (3). The greatest estimated number of incident cases in 2019 was in the high SDI quintile; whereas the highest estimated number of deaths and DALYs (Disability-adjusted life years) were in the middle SDI quintile [3]. The low and low-middle SDI quintiles have seen the greatest increases in the burden of cancer over the past ten years [3]. These projections are essential for achieving important SDG (United Nations (UN) Sustainable Development Goals) goals for lowering the burden of noncommunicable diseases like cancer and increasing equity in global cancer outcomes [3]. 14,61,427 incident cases of cancer were determined to be the predicted average in India for 2022. (Crude rate:100.4 per 100,000). In India, one in nine individuals has a lifelong risk of developing cancer. The most common cancers in men and women, respectively, were lung and breast cancers. Lymphoma was the most common site among children (0–14 years) with cancer (boys: 29.2%; girls: 24.2%). According to estimates, there will be 12.8% more cancer instances in 2025 than there were in 2020 [4]. Breast cancer is a metastatic cancer that is incurable and frequently metastasizes to remote organs such as the bone, liver, lung, and brain. A favorable outlook and a high survival rate can result from early diagnosis of the illness. Numerous genes have been associated with breast cancer. Unusual proliferation, oncogene and anti-oncogene mutations, and tumor progression are all impacted by these factors. Breast cancer related genes 1 and 2 are two well-known anti-oncogenes that decrease the likelihood of breast cancer (BRCA1 and BRCA2). The BRCA genes are situated on chromosomes 13q12 and 17q21, accordingly. They both encode proteins that inhibit tumor growth. Lack of BRCA1 causes abnormal centrosome duplication, genetic instability, dysregulation of the cell cycle checkpoint, and ultimately apoptosis. The human chromosome 17 long arm contains the human epidermal growth factor receptor 2, also known as c-erbB-2, an essential oncogene in breast cancer (17q12). The EGFR gene is located on chromosome 7's short arm. In people, it is also known as c-erbB-1 or Her1 (7p12). The EGFR protein is activated by binding to molecules like EGF, TGF-, amphiregulin, betacellulin, and others. It is a constituent of the tyrosine kinase family of cell surface glycoproteins. To promote cell proliferation, invasion, angiogenesis, and cell survival against apoptosis, the PI3K, Ras-Raf-MAPK, and JNK downstream signaling pathways of EGFR are activated. The most common and well-known family of 17 poly (ADP-ribose) polymerase enzymes in humans is known to heal single-strand breaks (SSBs) and double-strand breaks (DSBs). PARP-1 is also a DNA damage sensor. The expression of PARP-1 is upregulated in cancer cell lines and patients' tissues, according to numerous researches. Despite being primarily found in the nucleus, researchers have also looked at PARP-1's cytosolic distribution [5]. The DDR process involves five pathways, and BRCA1 and PARP-1 are both crucial steps in each one. As a means of repairing SSBs, PARP-1 employs the base excision repair mechanism. The two complementary systems that mediate repair in the case of the more harmful DSBs are the homologous recombination (HR) repair system, mediated among other DNA damage agents by BRCA1, and the non-homologous end joining (NHEJ), which is more error-prone and can also depend on PARP activity. Surprisingly, mounting evidence supports PARP's multifaceted functions and the interaction of the repair pathways by indicating that PARP-1 is also crucial in the HR process. A SSB will be caused by the administration of PARP inhibitors, and HR will fix it. When this SSB hits the replication fork, however, it will cause a DSB in the HR-deficient (BRCA-mutated) cells. The cell will die as a result of the accumulation of DSBs because it will result in apoptosis or mutation formation that ups the likelihood of getting cancer [6]. As of 2021, the US Food and Drug Administration (FDA) and the European Medicine Agency (EMA) have approved four PARP-1 inhibitors as anti-cancer treatments for breast or ovarian cancer [Table 1].

Table 1 FDA and EMA approved PARP1 inhibitors

S. No	PARP1 Inhibitor	IC50	Ref
1	Olaparib	13 nM	7
2	Niraparib	35 nM	7
3	Rucaparib	80 nM	7
4	Talazoparib	3 nM	7

Activation and the role of PARP-1

The revelation that PARP-1 is a DNA binding protein led to the hypothesis that it might be participated in DNA rebuild [7]. When DNA damage is minimal, PARP-1 role as a survival factor, and in a multiple DNA repair mechanisms, including base excision, single strand break, and double strand break repair pathways, have been linked to PARP-1 ([Figs. 1] to [4]). PARP is turned on when nicks form in DNA molecules [8] [9] [10] [11] [12] [13]. By means of the second zinc finger domain, PARP-1 binds to damaged DNA to create homodimers that catalyze, NAD⁺ is broken down into nicotinamide and ADP-ribose. [8] [9]. In response to activation, PARP-1 attaches to DNA breaks., NAD⁺ is split into nicotinamide and ADP-ribose moieties, and the latter is then polymerized onto glutamic acid residues of several nucleus acceptor proteins, including PARP-1 [9] [11] [12] [13] [14]. When DNA is only slightly damaged, PARP-1 takes part in the DNA repair process, which allows the cell to survive [8] [9] [10] [11] [13]. However, in situations where there has been significant DNA destructed, PARP-1 overactivation results in a drop in NAD⁺ and ATP levels, which causes dysfunctional cells and mortality [9] [11] [14]. As a result, overactivation of PARP has been linked to the pathogenesis of numerous illnesses, such as cerebro-vascular disease, reperfusion injury and cancer resistance [15]. This ADP- ribose is then used by PARP-1 to synthesis branched nucleic acid like polymers called Poly (ADP- ribose). Covalent interactions are formed between this and nuclear proteins like histones, topoisomerase, endonucleases, etc. [8] [9] [10] [14]. A large number of PARP-1 inhibitors have been developed as a result of the importance of PARP-1 in DNA repair as a therapeutic target for the therapy of cancer [12] [16]. The ability to behave as a stand-alone therapy to eradicate cancer cells with homologous recombination (HR) DNA repair deficiencies, such as those who have tumor suppressor gene loss-of-function variants in either BRCA1 or BRCA2 [17]. Through BER, DNA fractures are repaired. In addition, PARP plays in a wide range of other nuclear functions, such as facilitating HR [18]. Base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR), which are the main mechanisms to resolve SSB, are among the at least 5 main DNA damage repair mechanisms operating in mammalian cells [18] [19]. The two pathways for repairing DSB are homologous recombination (HR) and nonhomologous end joining (NHEJ). A homological arrangement of chromosomes close to the area of the damage serves as an arrangement for HR, a high repair system, to ensure accurate restoration of the DNA sequence [13]. NHEJ joins unrelated DNA strands after dissecting DNA damage, changing nucleotide sequences and causing gene rearrangements as a result. It is an error-prone pathway with reduced fidelity. DSB are damaging lesions to cells that are challenging to heal [18] [19]. Reports that cell lines deficient in BRCA1 and BRCA2 (proteins involved in homologous recombination (HR) repair) are extremely susceptible to PARP-1 inhibitors resulting in cell death further highlighted the potential of PARP inhibition within oncology. The wild-type alleles of the recognised tumour suppressor genes BRCA1 and BRCA2 are commonly lost in the tumours of heterozygous carriers. Breast cancer is known to be associated with both BRCA1 and BRCA2 protein abnormalities. Ovarian, prostate, and pancreatic cancers are also more likely to affect carriers of BRCA1 and BRCA2 variants [20]. By inhibiting PARP-1, the cancer cells are unable to repair their damaged DNA, leading to their death. PARP-1 inhibitors have shown promising results in the treatment of breast cancer, particularly in those with BRCA mutations, which are associated with a high risk of developing breast and ovarian cancers. These inhibitors have been approved for use in combination with chemotherapy for the treatment of advanced ovarian cancer and are being studied for their potential in the treatment of breast cancer[21] [22]. As a result of PARP-1's crucial role in DNA damage repair, numerous small molecules that target its catalytic domain have been created as stand-alone therapies (synthetic lethal) or as chemo-sensitizers in combination with ionising radiation or DNA-damaging chemotherapeutic agents to kill cancer cells that lack DNA repair mechanisms [22]. PARP inhibitors have been used in cancer therapy as both chemo and radio-sensitizers, more recently, have been employed alone in treatment of tumors displaying BRCA mutations [23].

Fig. 1 Activation of PARP-1 inhibitor

Fig. 2 Function of PARP-1

Fig. 3 Function of PARP-1 and DNA repair

Fig. 4 Mechanism of PARP-1 inhibitor

Structure of PARP-1

PARP-1 is an enzyme that plays a key role in DNA repair, genomic stability, and cell survival. It is a member of the Poly (ADP-ribose) polymerase (PARP) family of enzymes, which are involved in cellular responses to DNA damage [8] [9] [10]. PARP-1 is a 116-kDA protein that has three principal domains, the structure of PARP-1 is made up of multiple domains, including an N-terminal DNA-binding domain, a central catalytic domain, and a C-terminal auto-modification domain. The DNA-binding domain helps the enzyme recognize and bind to DNA strand breaks, while the catalytic domain contains the active site responsible for synthesizing poly (ADP-ribose) chains. The auto-modification domain allows for the self-modification of PARP-1, which is important for its activity and regulation [24]. Multiple DNA repair processes, including base excision, single strand break, and double strand break repair pathways, have been linked to PARP-1. PARP is activated when nicks form in DNA molecules. Through the second zinc finger domain, PARP-1 binds to damaged DNA to generate homodimers that catalyse the cleavage of NAD+ into nicotinamide and ADP-ribose. Then, using ADP-ribose, it creates poly (ADP-ribose), which resembles branched nucleic acids and makes covalent bonds with nuclear proteins including histones, topoisomerase, endonucleases, etc., [24]. Zinc finger NLS- Binds to DNA strand breakage

Auto-modification domain- Mediates for protein-protein interaction, Catalytic domain- Nucleic acid binding motif [24].

[Fig. 5] PARP structure and function. PARP contains an NH₂-terminal (N-term) DNA binding domain, an auto-modification domain and a COOH-terminal (C-term) catalytic domain. Zinc finger motifs (Zn) recognize and bind damaged DNA, activating the catalytic function that polymerizes poly (ADP-ribose) (PAR) from NAD⁺ [24]. The function of PARP-1 is to detect and respond to DNA damage by synthesizing poly (ADP-ribose) chains on target proteins. This process is called poly (ADP-ribosylation) and it serves as a signal for DNA repair processes, such as base excision repair and homologous recombination, to occur. In addition, PARP-1 also plays a role in regulating cell death by controlling the activation of apoptosis, or programmed cell death [8] [9] [10] [14].

Fig. 5 PARP structure and function

PARP-1 inhibitors in breast cancer

PARP-1 inhibitors constitute a pharmacological category of medications that have demonstrated encouraging outcomes in the management of breast cancer, particularly in instances when distinct genetic alterations are detectable [25]. Poly(ADP-ribose) polymerase 1 (PARP-1) is an enzymatic protein that plays a crucial role in the process of DNA repair [26]. In the context of cancer treatment, PARP-1 inhibitors function by impeding the activity of this enzyme, hence hindering its ability to carry out its reparative functions. Consequently, this inhibition results in the accumulation of DNA damage within cancerous cells [27]. BRCA1 and BRCA2 mutations are widely recognized as prominent genetic alterations linked to breast cancer[28]. The presence of these mutations hinders the functionality of DNA repair mechanisms within cells, rendering them more vulnerable to subsequent DNA damage. PARP inhibitors exploit this vulnerability by additionally suppressing DNA repair mechanisms, leading to the demise of cancerous cells [29]. PARP inhibitors have demonstrated substantial advantages in the management of breast cancer, namely among individuals harboring BRCA1 or BRCA2 mutations, alongside additional impairments in DNA repair mechanisms [30]. The efficacy of PARP inhibitors in the treatment of advanced breast cancer has been substantiated by clinical trials, which have shown significant enhancements in terms of progression-free survival and overall survival for patients[31]. Several PARP inhibitors that have been approved by the Food and Drug Administration (FDA) for the treatment of breast cancer include:

Olaparib ([Fig. 6(a)]), commercially known as "Lynparza," is a pharmacological agent classified as a PARP-1 inhibitor [32]. The oral medicine in question has been jointly developed by AstraZeneca and Merck & Co. (referred to as MSD internationally, except the United States and Canada). Its primary use lies in the treatment of several forms of cancer, notably ovarian and breast cancer, specifically targeting distinct genetic abnormalities [32]. Lynparza (Olaparib) functions by the inhibition of PARP enzymes, specifically PARP-1, which play a crucial role in the cellular DNA repair process [33]. The suppression of poly(ADP-ribose) polymerase (PARP) in cancer cells with certain genetic abnormalities, such as BRCA1 or BRCA2 mutations, or exhibiting deficits in DNA repair pathways, results in the accumulation of DNA damage and subsequent induction of cell death [34]. The targeted therapeutic strategy of Olaparib is founded on the principle of synthetic lethality, wherein cancer cells with compromised DNA repair processes are specifically eliminated through the use of PARP inhibitors. Lynparza has been granted approval by the U.S. Food and Drug Administration (FDA) for multiple indications, which include: The maintenance therapy for adult individuals with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have achieved either complete or partial response after chemotherapy based on platinum is being discussed. The maintenance therapy for adult individuals diagnosed with advanced ovarian cancer, who exhibit a complete or partial response to first platinum-based chemotherapy, and possess the BRCA1 or BRCA2 genetic mutation, is indicated. The focus of this study is to investigate the therapeutic interventions for adult individuals afflicted with deleterious or presumed detrimental germline BRCA-mutated HER2-negative metastatic breast cancer, who have undergone prior chemotherapy treatments [35]. The focus of this study is to investigate the therapeutic interventions for adult individuals diagnosed with advanced ovarian cancer, specifically those with germline BRCA mutations. The target population comprises patients who have undergone three or more rounds of chemotherapy prior to the study. Lynparza has exhibited substantial clinical advantages in these particular cohorts of patients, resulting in its authorization as a focused therapeutic intervention for ovarian cancer and breast cancer characterized by BRCA mutations. Like all medications, Lynparza can potentially cause negative effects, therefore it is important for a skilled healthcare provider to closely monitor its usage. Individuals who are contemplating the use of Lynparza as a treatment option should engage in a comprehensive discussion with their oncologist regarding the potential advantages and disadvantages associated with this medication. This dialogue is crucial in order to establish the most suitable course of treatment tailored to their unique medical circumstances [36].

Fig. 6 Structure of Olaparib (a), Niraparib (b), Talazoparib (c), and Rucaparib (d).

Niraparib ([Fig. 6(b)]), commercially referred to as "Zejula," is a pharmacological agent classified as a PARP-1 inhibitor [37]. The medication in question is an oral pharmaceutical product that has been produced by the pharmaceutical company GlaxoSmithKline (GSK). It is primarily employed in the therapeutic management of specific forms of cancer, with a particular focus on advanced ovarian cancer as well as recurrent ovarian, fallopian tube, or primary peritoneal cancer [38]. Zejula (Niraparib) functions through the inhibition of PARP-1 and other PARP enzymes, which play a crucial role in the cellular DNA repair process [39]. The suppression of PARP in cancer cells harboring certain genetic abnormalities, such as BRCA1 or BRCA2 mutations, or other impairments in DNA repair pathways, results in the accumulation of DNA damage and subsequent cellular demise [40]. The phenomenon under discussion is commonly referred to as synthetic lethality, wherein cancer cells exhibiting compromised DNA repair pathways are specifically targeted for elimination through the administration of PARP inhibitors. The approval of Zejula by the U.S. Food and Drug Administration (FDA) pertains to its use as a maintenance treatment for adult patients who have experienced a recurrence of epithelial ovarian, fallopian tube, or primary peritoneal cancer and have achieved either a complete or partial response to platinum-based chemotherapy [39]. Additionally, this medication has been authorized for the purpose of maintaining the treatment of individuals who have recently been diagnosed with ovarian cancer, have undergone chemotherapy with platinum-based agents, and have exhibited either a complete or partial response to said treatment [41]. The targeted medication known as Niraparib (Zejula) has demonstrated substantial therapeutic advantages in several patient populations, resulting in its approval for the treatment of ovarian cancer. For patients who have experienced a recurrence or have recently been diagnosed with ovarian cancer, as well as those who possess specific genetic abnormalities linked to deficits in DNA repair, this alternative is considered indispensable. Like all medications, Zejula may have negative effects, and its administration should be closely supervised by a skilled healthcare professional. Individuals who are contemplating the utilization of Zejula as a treatment option should engage in a discussion with their oncologist regarding the potential advantages and disadvantages associated with the drug. This dialogue is crucial in order to establish the most suitable course of treatment tailored to their particular medical condition.

Talazoparib ([Fig. 6(c)]), commercially marketed as "Talzenna," is a pharmacological agent classified as a PARP-1 inhibitor [42]. The oral medicine in question has been produced by Pfizer and is employed for the therapeutic management of specific forms of cancer, including HER2-negative advanced breast cancer characterized by distinct genetic alterations. Talzenna (Talazoparib) functions in a manner akin to other inhibitors of PARP-1, effectively impeding the enzymatic activity of PARP enzymes, specifically PARP-1, which play a crucial role in the process of DNA repair [43]. The suppression of PARP in cancer cells harboring certain genetic abnormalities, such as BRCA1 or BRCA2 mutations, or other impairments in DNA repair pathways, results in the accumulation of DNA damage and subsequent cell death [44]. Talazoparib, like to other inhibitors of poly (ADP-ribose) polymerase (PARP), capitalizes on the principle of synthetic lethality to specifically target cancer cells that possess compromised DNA repair systems [45]. Talzenna has been granted approval by the U.S. Food and Drug Administration (FDA) for the therapeutic management of adult individuals diagnosed with metastatic breast cancer that is HER2-negative and characterized by deleterious or suspected harmful hereditary BRCA mutations. It is imperative that these individuals have received prior chemotherapy treatment in the neoadjuvant, adjuvant, or metastatic context. The clinical efficacy of talazoparib has been demonstrated in a distinct subset of patients, resulting in its authorization as a targeted therapeutic approach for advanced breast cancer characterized by BRCA mutations. Like all medications, Talzenna may have adverse effects, and its use should be closely supervised by a skilled healthcare professional. Patients who are contemplating the use of Talzenna should engage in a discussion with their oncologist regarding the potential advantages and disadvantages of the treatment in order to ascertain the most suitable course of action for their individual medical condition.

Rucaparib ([Fig. 6(d)]), commercially known as "Rubraca," is a pharmacological agent classified as a PARP-1 inhibitor [46]. The oral medicine, created by Clovis Oncology, has been designed for the treatment of specific forms of cancer, notably ovarian cancer and prostate cancer, that have distinct genetic abnormalities. Rubraca (Rucaparib) functions in a manner akin to other inhibitors of poly (ADP-ribose) polymerase 1 (PARP-1) by impeding the enzymatic activity of PARP enzymes, particularly PARP-1, which play a role in the repair of DNA [47]. The suppression of PARP in cancer cells harboring certain genetic abnormalities, such as BRCA1 or BRCA2 mutations, or other impairments in DNA repair pathways, results in the accumulation of DNA damage and subsequent cell death [44]. Rucaparib, like to other inhibitors of poly (ADP-ribose) polymerase (PARP), exploits the principle of synthetic lethality to specifically target neoplastic cells that possess compromised DNA repair pathways [48]. Rubraca has been granted approval by the U.S. Food and Drug Administration (FDA) for many indications, which encompass: The maintenance therapy for adult individuals with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have achieved either complete or partial response to chemotherapy based on platinum is indicated [49]. The objective of this study is to investigate the therapeutic interventions for adult individuals diagnosed with advanced ovarian cancer that is linked with detrimental BRCA mutations, whether inherited or acquired, and who have previously had at least two rounds of chemotherapy. The focus of this study is on the management of adult individuals diagnosed with advanced ovarian cancer that is accompanied with detrimental BRCA mutations, whether inherited or acquired, and who have previously undergone one or more rounds of chemotherapy. The objective of this study is to examine the therapeutic interventions for adult individuals diagnosed with advanced ovarian cancer that is associated with detrimental BRCA mutation, either in the germline or somatic cells. Furthermore, this investigation aims to focus on patients who have previously undergone one or more rounds of chemotherapy. This indication is primarily intended for individuals who have seen disease progression at least six months following their most recent administration of platinum-based chemotherapy. Rubraca has exhibited substantial clinical advantages in these particular cohorts of patients, hence resulting in its authorization as a targeted therapeutic approach for ovarian cancer and specific forms of prostate cancer characterized by BRCA mutations. Like all medications, Rubraca has potential side effects and should be closely monitored by a skilled healthcare professional. Individuals who are contemplating the use of Rubraca as a treatment option should engage in a comprehensive discussion with their oncologist regarding the potential advantages and disadvantages associated with this medication. This dialogue will aid in the identification of the optimal treatment strategy tailored to their unique medical circumstances.

These medications are commonly provided to individuals who possess BRCA mutations, and in certain instances, to those exhibiting defects in other DNA repair pathways. Furthermore, current investigations are being conducted to examine the potential of PARP inhibitors in conjunction with other therapeutic modalities, including chemotherapy or immunotherapy, with the aim of augmenting their effectiveness. It is noteworthy to acknowledge that although PARP inhibitors have demonstrated substantial advantages in certain instances of breast cancer, their efficacy may not extend universally to all individuals. Like all forms of cancer treatment, the formulation of personalized treatment regimens that take into account the patient's unique genetic profile and medical history is crucial in order to optimize treatment outcomes. Hence, it is imperative to seek guidance from a certified oncologist in order to ascertain the most appropriate treatment strategy for individual patients diagnosed with breast cancer.

1,2,4-triazoles

A collection of new compounds with 1,2,4-triazole scaffolds that have been variously substituted with different moieties was taken into consideration. The polynitrogen-based bioisosteres was used in replace of the cyclic amide pharmacophore (i.e, triazole-thiones and alkylsulfanyl-triazoles). As a result, a thorough in-silico process was carried out to examine the putative binding mode of the derivatives within the catalytic domain of PARP-1. A total of six hits with high binding affinities were chosen, made, and scaled up for biological testing. These substances were examined for their capacity to inhibit the PARP-1 enzyme's activity before being put through a cytotoxicity test on the MCF-7 cell type. Moreover, wound healing tests were used to evaluate the inhibition of cell migration and invasion [50].

2,3-Difluorophenyl-Linker-Containing PARP-1 Inhibitors

Studies on Olaparib, the first medication authorised to treat some ovarian cancers, revealed that the N-substituted piperazine was flexible but the phthalazine fragment was necessary for PARP-1 inhibition potency [9]. Olaparib was discovered to have inferior antitumor efficacy as other PARP inhibitors rose to prominence [51]. A novel 2,3-difluorophenyl-linker analogue was created and fluorine was added to Olaparib's phenyl linker at position 3 in an effort to increase its antitumor effectiveness. In contrast to Olaparib, molecular docking analysis revealed that Tyr889 and both the 3-position and 2-position fluorine atoms of the analogue made a hydrogen bond. In order to investigate the structure-activity relationship (SAR) of the 2,3-difluorophenyl-linker analogues of Olaparib, a novel series of 2,3-difluorophenyl-linker analogues derived from Olaparib was designed. It was then thoroughly evaluated to determine if the type of substituent at the terminal nitrogen of the piperazine would enhance pharmacological activity. Finally, a highly potent PARP-1 enzymatic inhibitor 2-(4-(2,3-Difluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pipe-razin-1-yl)nicotine nitrile with excellent in vitro and in vivo antitumor efficacy against both BRCA1- and BRCA2-deficient tumour cells, good specificity for BRCA-deficient cells and a good safety profile was identified as a unique candidate compound for the development of antitumor drug [50].

Apigenin-Piperazine Hybrid

It has been claimed that Amentoflavone (AMF) is a specific PARP-1 inhibitor that to AMF has undergone structural changes and trimming resulting in a number of AMF variants and apigenin-piperazine/piperidine hybrids. One of these compounds had a strong inhibitory impact on PARP-1 (IC₅₀ = 14.7 nM) and was highly selective for PARP-1 over PARP-2 (61.2- fold). The aforementioned compound immediately bound to the PARP-1 structure, as demonstrated by molecular dynamics modelling and the cellular thermal shift assay. Through the inhibition of PARP-1, studies conducted in vitro and in vivo revealed a powerful chemotherapy sensitising effect against A549 cells and a selective cytotoxic effect towards SK-OV-3 cells. additionally showed favourable safety margins, pharmacokinetic parameters, and acceptable ADME characteristics. These results showed that this could be a potential lead molecule for chemosensitizers and the (BRCA-1) deficient cancer therapy [10].

Benzo[de][1] [7] naphthyridin-7(8H)-ones

As new PARP-1 inhibitors, a group of benzo[de][1] [7] naphthyridin-7(8H)-ones with a functionalized long-chain appendage have been developed. The original attempt resulted in the first-generation PARP-1 inhibitors, which had a terminal phthalazin-1(2H)-one framework and remarkably high PARP-1 inhibitory activity (0.31 nM), but only moderate cell potency. Further research led to the development of the second-generation lead compound, which exhibits strong potency against the PARP-1 enzyme and BRCA-deficient cells (CC₅₀ 0.26 nM), particularly for the BRCA1-deficient MDA-MB-436 cells. The new PARP-1 inhibitors substantially reduced H₂O₂-triggered PARylation in SKOV3 cells, increased the accumulation of DNA double-strand breaks within the cell, and inhibited cell-cycle progression in BRCA2-deficient cells, according to mechanistic investigations. Additionally, a sizable potentiation of temozolomide's cytotoxicity was seen. the distinctive structural features and extraordinarily high potency and stood as a promising drug candidate [14].

4-(3-(2-(6-Amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,6,7,8-tetrahydropyrido-[3,4-d] pyrimidine-7-carbonyl)-4-fluorobenzyl) phthalazin-1(2H)

One comes out as the most promising candidate, with pIC₅₀ values higher than 8 and strong inhibitory activities against both PARP-1/2 and PI3K. 4-(3-(2-(6-Amino-4-(trifluoromethyl)pyridin-3-yl) is a compound. -4-morpholino-5,6,7,8-tetrahydropyrido-[3,4-d] pyrimidine-7-carbonyl)-4-fluorobenzyl) In cellular assays, phthalazin-1(2H)-one showed better antiproliferative profiles against cancer cells that were BRCA-deficient and BRCA-proficient. Comprehensive biochemical and cellular mechanistic studies have shed light on the clear synergistic effects caused by the simultaneous suppression of the two targets. In the MDA-MB-468 xenograft model, demonstrated more effective antitumor activity than the equivalent drug combination (Olaparib + BKM120), with a tumour growth inhibitory rate of 73.4% and no detectable toxic effects. According to all of the findings, is a first-generation dual PARP/PI3K inhibitor that is an extremely potent anticancer drug [16].

5-fluoro-1H-benzimidazole-4-carboxamide derivatives

Novel 5-fluorine-benzimidazole-4-carboxamide analogues were created and produced in a number of different ways. The ability of each specific substance to inhibit PARP-1 was tested. To assess the potentiation impact of cytotoxic agents against cancer cell lines, compounds with strong intrinsic PARP-1 inhibitory potency have been tested in vitro. These endeavours resulted in the discovery of the compound, which showed potentiation of temozolomide cytotoxicity in cancer cell line A549 (PF₅₀ = 1.6), excellent cell inhibitory activity in HCT116 cells (IC₅₀ = 7.4 nM), and strong inhibition against the PARP-1 enzyme with an IC₅₀ of 43. nM [52].

3-Oxo-2,3-dihydrobenzofuran-7-carboxamide

Optimization of ((Z)-2-benzylidene-3-oxo-2,3-dihydrobenzofuran-7-carboxamide, PARP-1 led to a tetrazolyl analogue (IC₅₀ = 35 nM) with improved inhibition. A promising new lead was produced by isosterically replacing the tetrazole ring with a carboxyl group (IC₅₀ = 68 nM). This lead was later optimised to produce analogues with strong PARP-1 IC₅₀ values (4–197 nM). The majority of compounds are selective towards PARP-2 and have IC₅₀ values that are similar to those of clinical inhibitors, according to PARP enzyme profiling. The mechanism of interaction with analogue appendages extending towards the PARP-1 adenosine-binding pocket was shown by X-ray crystal structures of the key inhibitors bound to PARP-1. Breast cancer gene 1 (BRCA1)-deficient cells were specifically killed by compound (Z)-3-Oxo-2-(4-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1] [2] [4]-triazolo[4,3-a] pyrazine-7-carbonyl)benzylide ne)-2,3-dihydrobenzofuran-7-carboxamide, an isoform-selective PARP-1/-2 (IC₅₀ = 30 nM/2 nM) inhibitor, in contrast to isogenic BRCA1-proficient cells [19].

Substituted 2-phenyl-2H-indazole-7-carboxamides

A series of potent substituted 2-phenyl-2H-indazole-7-carboxamides were developed and evaluated as poly (ADP-ribose) polymerase inhibitors (PARP). The result of this thorough SAR investigation was the discovery of the substituted 5-fluoro-2-phenyl-2H-indazole-7 carboxamide analogue, which demonstrated excellent PARP enzyme inhibition with IC₅₀ = 4 nM, inhibited proliferation of cancer cell lines lacking BRCA-1 with CC₅₀ = 42 nM, and demonstrated encouraging pharmacokinetic properties in rats compared to other lead [53]. The details of structures and IC₅₀ values of compounds were presented in [Table 2].

Table 2 Synthetic derivatives with their structures and IC₅₀ values

S. No	Name of the compounds	Structure	IC50	Ref
1,2,4-triazoles
1	5-(1H-indol-2-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol		517.98 nm	28
2	3-(All-1-ylsulfanyl)-5-((1-all-1-yl)-indol-2-yl)-4-phenyl1,2,4-triazole		665.42 nm	28
2,3-Difluorophenyl-Linker analogues
3	2-(4-(2,3-Difluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pipe -razin-1-yl)nicotinonitrile		1.3±0.3 nm	29
Apigenin−Piperazine Hybrid
4	5,7-dihydroxy-2-(4-hydroxyphenyl)-8-((4-thiophene-2-ylmethyl)piperzin-1-yl)methyl)-4H-chromen-4-one		14.7 nm	30
Benzo[de] [1] [7] naphthyridin-7(8H)-ones
5	4-(3-(2-(6-Amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,6,7,8-tetrahydropyrido-[3,4-d]pyrimidine-7-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one		3.46 nm	31
3-Oxo-2,3-dihydrobenzofuran-7-carboxamide
6	(Z)-3-Oxo-2-(4-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1] [2] [4]- triazolo[4,3-a]pyrazine-7-carbonyl)benzylidene)-2,3 dihydrobenzofuran-7-carboxamide		30 nm	34
2-Phenyl-2H-indazole-7-carboxamides
7	2-(4-(azetidine-3-carboxamido)-3-fluorophenyl)-5-fluoro-2H-indazole-7-carboxamide		04 nm	35

PARP-1 and pathological disorders

PARP-1 is an essential nuclear enzyme that assumes a pivotal function in multiple cellular activities, principally encompassing DNA repair mechanisms and the preservation of genomic stability. The aforementioned entity belongs to the PARP gene family, comprising a collection of enzymes that facilitate the transfer of ADP-ribose units from nicotinamide adenine dinucleotide (NAD+) to certain proteins, including the enzymes themselves. Poly(ADP-ribosyl)ation, a biochemical process, plays a crucial role in the regulation of diverse cellular activities. DNA damage can arise from a multitude of factors, encompassing exposure to radiation, chemical agents, and oxidative stress. The activation of PARP-1 occurs in response to the occurrence of DNA strand breaks, whereby its primary function is to attract DNA repair proteins to the specific areas of damage, so aiding in the facilitation of the repair process. PARP-1 plays a crucial role in preserving the stability of the genome and mitigating the potential for the development of pathological conditions, such as cancer and other disorders, by facilitating the repair of DNA damage and preventing the accumulation of mutations. Nevertheless, although PARP-1 plays a critical role in the process of DNA repair, excessive activation of this enzyme can lead to disastrous outcomes. In instances of significant DNA damage, the overactivation of PARP-1 can result in the depletion of cellular NAD+ and ATP, leading to an energy deficit and subsequent cell demise. This phenomenon is commonly referred to as PARP-1 hyperactivation-induced necrosis. This phenomenon holds significant relevance within specific clinical states and disorders. The involvement of PARP-1 in pathological illnesses, particularly in cancer therapy, has been extensively researched, with a specific focus on PARP inhibitors, as previously indicated. PARP inhibitors have been formulated with the specific objective of selectively targeting cancer cells that have deficits in DNA repair mechanisms, such as those harboring BRCA mutations. The function of these inhibitors involves the obstruction of PARP-1's enzymatic activity, resulting in synthetic lethality inside cancer cells that possess impaired DNA repair pathways. However, these inhibitors do not harm normal cells that possess complete DNA repair processes. In addition to its involvement in cancer, PARP-1 has also been associated with many clinical conditions, such as neurological diseases. Neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, are characterized by the presence of DNA damage, oxidative stress, and compromised DNA repair mechanisms. The possible therapeutic method of inhibiting PARP-1 has been investigated in the context of countering neurodegeneration and safeguarding neurons against death caused by DNA damage. In brief, the proper functioning of PARP-1 is crucial for the preservation of genomic integrity and the repair of DNA lesions. However, the disruption and excessive activation of PARP-1 have been implicated in the development of diverse clinical conditions. Conversely, the focused suppression of PARP-1 in particular pathological scenarios, such as cancer cases characterized by impaired DNA repair mechanisms, has exhibited encouraging outcomes as an approach to therapy. Further investigation is required in order to comprehensively comprehend the intricate functions of PARP-1 in diverse clinical contexts and to investigate the possible therapeutic advantages of PARP inhibitors in a range of disorders other than cancer.

PARP-1 and neurodegenerative diseases

Progressive memory loss and motor dysfunction are hallmarks of neurodegenerative diseases. Among their pathological symptoms are the accumulation of insoluble proteins in brain deposits, Tau-formed neurofibrillary tangles in the brains of AD patients, and irreversible neuronal malfunction or death [54] [55] [56]. The function of PARP-1 in neurodegenerative disorders has recently been studied. They demonstrated that -synuclein accumulating in neurons activates PARP-1, and PARylation makes -synuclein more toxic, accelerating neuronal mortality. Ataxia-telangiectasia (A-T) mouse and worm models showed elevated amounts of PARylation and markedly dysfunctional mitochondria. It's interesting to note that PARP-1 reduction reduces A-T neuropathology and enhances neuromuscular performance [55] [57] [58]. As with other neurodegenerative illnesses like HD, ALS, and multiple sclerosis, excessive activation of PARP-1 has been linked to these conditions. The signs of disease can be improved by PARP-1 inhibition [59] [60] [61].

PARP-1 and Parkinson’s disease

Another typical neurodegenerative illness, Parkinson's disease primarily effects the motor system and is frequently associated with cognitive dysfunction and abnormal behaviour. The loss of dopaminergic (DA) neurons in the substantia nigra and the development of Lewy bodies, which are closely linked to mitochondrial dysfunction and α-synuclein aggregation, are two pathological signs of Parkinson's disease (PD). Recent research suggests that PARP-1 affects PD development. In line with the notion that aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2)-mediated activation of PARP-1 is one of the primary causes for the loss of DA neurons, PARP-1 activation is a crucial early event in DA neuronal cell death induced by 6-OHDA [55] [62] [63] [64]. Lewy bodies contain both AIMP2 and -synuclein, and AIMP2 can directly interact with and trigger PARP-1. Similar to this, activated PARP-1 can control a number of pathological PD processes, such as α-synuclein aggregate formation, mitochondrial dysfunction, and mitophagy dysregulation [65] [66] [67]. Nitric oxide synthase is activated when pathological α-synuclein (in the shape of an oligomer or an insoluble fibre) is present. This causes DNA damage and PARP-1 activation. By altering NAD+ stores and energy metabolism, activated PARP-1 affects mitochondrial function. This is accompanied by depolarization of the mitochondrial membrane potential brought on by PARylation [57] [68]. There are many chemicals that are thought to be sporadic PD pathogenic agents. The standard drug for creating PD rodent models, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, causes oxidative stress in old mice, which is followed by the activation of PARP-1 by Ca2+-dependent enzymes [69]. Additionally, following the silencing of vacuolar protein sorting-associated protein 35, PARP-1 is increased and inhibition of RNF146 or other pathological PD alterations. The failure of the intracellular process known as mitophagy, which removes damaged mitochondria, is linked to Parkinson's disease (PD). Parkin and PINK1 are both involved in mitophagy, and abnormalities in PARK6 (PINK1) or PARK2 (parkin) lead to autosomal recessive Parkinson's disease (PR) [64] [70] [71] [72] [73]. Research revealed that by blocking SRIT1, PARP-1 may be involved in mitophagy. Despite being more commonly associated with the nucleus, PARP-1 can also be found in the mitochondria, where it PARylates proteins in the electron transport chain and is involved in the repair of mitochondrial DNA. Similar to nuclear PARP-1, overactivation of mitochondrial PARP-1 (mtPARP-1) prevents mitochondrial biogenesis, which results in the demise of neuronal cells [74] [75] [76]. Neuroinflammation, dysregulated autophagy, and irregular sleep patterns are additional PARP-1-related causes of PD. Both the migration of high mobility group box 1 and the regulation of NF-B transcriptional activity are ways that PARP-1 causes the neuroinflammation of PD (HMGB1). Particularly, engaged PARP-1 inhibits SIRT1 and increases HMGB1's acetylation, which promotes HMGB1 release from cells. HMGB1 can act in the extracellular milieu in a proinflammatory cytokine-like way, activating microglia, compromising BBB, and encouraging the expression of inflammatory cytokines, all of which contribute to the onset of Parkinson's disease (PD). Importantly, PD in rodents has been treated with an anti-HMGB1 monoclonal antibody. This therapy was able to significantly reduce oxidative stress, keep DA neurons in the substantia nigra, and enhance mouse motor performance [64] [77] [78] [79]. Therefore, inhibiting PARP-1 may be a useful strategy for the therapy of Parkinson's disease [55]. As was already stated, autophagy is essential for maintaining the brain's regular function. Toxic clumps can be removed by upregulated autophagy, which is also helpful for reducing inflammation in conditions affecting the central nervous system. In PD, impaired autophagy can add to the build-up of -synuclein, which may cause DA neurons to degenerate. Similar to this, activated PARP-1 speeds up -synuclein aggregation and increases its neurotoxicity in primary rodent cortical neurons. It has been demonstrated that excessive PARP-1 activation causes autophagy dysfunction by triggering the mTOR pathways and PARylating transcription factor EB, which inhibits the transcription of genes linked to autophagy like LC3-II. In particular, PARP-1 reduction can boost autophagy activity, causing -synuclein to break down [55] [64] [80] [81].

PARP-1 and Alzheimer's disease

Short-term memory loss is an early sign of Alzheimer's disease (AD), the most prevalent neurological illness. Growing data suggests that tau tangles, Aβ plaque deposition, and hippocampal neuronal loss are typical neuropathologies of AD [82] [83] [84]. It has been demonstrated that in the brains of AD patients, PARP-1/PAR co-localizes with A, Tau, and microtubule-associated protein 2 (a branching marker). With the production of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS), AD and A both boost PARP-1 activity. A deposition by activated PARP-1 can exacerbate AD symptoms; as a result, PARP-1 can be triggered both before and after Aβ. Excessive PARP-1 activation was viewed as an important and early change in the pathogenesis of AD [85] [86] [87] [88]. However, reduced nucleolar PARP-1 activated DNA cytosine-5-methyltransferase 1 and suppressed rDNA, serving as an early indicator of cognitive decline in AD. Although the research concentrated on nucleolar PARP-1 in hippocampal pyramidal cells, it was found that AD patients complete brains, especially the frontal and temporal lobes, expressed PARP-1 [89] [90]. It is believed that persistent neuroinflammation speeds up the development of neurodegeneration in AD. According to some reports, the NF-kB subunit RelA can induce neuroinflammation through PARylation. When there is AD pathology present, activated PARP-1 encourages NF-kB to attach to DNA in microglia. Parallel to this, a number of studies have shown that inhibiting PARP-1 can halt the development of AD [91] [92] [93] [94]. In mice lacking PARP-1, Aβ-induced microglial activation is reduced. In the AD rodent model, treatment with PJ34 (a PARP-1 inhibitor) may reduce microglial activation and neurodegeneration. Overall, PARP-1 is essential for the inflammatory process connected to AD [95] [96]. In numerous AD models, SIRT1 functions as a neuroprotective component. It controls the progression of AD by preventing the build-up of A and reducing cognitive loss brought on by ageing [97] [98]. Notably, after the addition of NAD+ and SIRT1 agonists, a sizable decrease in DNA damage in AD was seen. In AD, PARP-1 and SIRT1 contend with one another for a limited supply of NAD+ [99] [100] [101]. Previous research has demonstrated that BBB leaking occurs in the early stages of AD and may be a factor in dementia and cognitive decline [102]. The BBB's permeability increased as a result of A deposition in the walls of arterioles and capillaries, which was verified by autopsy on the brains of AD patients. In this way, PARP-1 is involved in preserving the structure of the BBB [103]. That is, by encouraging the expression of tight junction proteins, inhibition of PARP-1 improves barrier stability. Furthermore, the suppression of PARP-1 reduces the endothelial dysfunction brought on by neuroinflammation, indicating that inhibiting PARP-1 may lessen cognitive impairment by preserving the integrity of the BBB (88). All of these data point to a critical function for PARP-1 in the development of AD [55].

PARP-1 in diabetes mellitus

Pancreatic beta cell death causes type 1 diabetes, also known as insulin-dependent diabetes mellitus, an autoimmune disease [104]. The role of PARP activation in the process of cell death has been the topic of in-depth research for the past 20 years. Cell toxins, streptozotocin, and alloxan-induced release of various inflammatory cell mediators like cytokines and free radicals all functionally inhibit and eventually destroy islets of Langerhans isolated from rats, mice, or humans. Numerous investigations have looked into the function of PARP in these processes using different pharmacological enzyme inhibitors. Streptozotocin application induces DNA strand breaks and PARP activation in separated mouse and rat islets, a reduction in NAD+ and proinsulin content, and an inhibition of insulin secretion [105] [106] [107]. The beta cell degeneration was prevented by the PARP inhibitors 3-aminobenzamide, nicotinamide, INH2BP, PJ34, and piclonamide because they reduced beta cell NAD+ levels and attenuated hyperglycemia [108] [109] [110]. The effects of PARP inhibition on complications brought on by diabetes have also been examined. PARP inhibitors like INO-1001 and PJ34 have been investigated for their effects on the progression of diabetic nephropathy in Lepr(db/db) (BKsJ) mice, an experimental model of type 2 diabetes [111]. Both medications reduced diabetes-related albumin excretion and mesangial expansion as well as prevented hyperglycemia. Additionally, PJ34 has been shown to be efficacious when administered orally to rats with a rat model of early diabetic neuropathy [112]. Evidence suggests that streptozotocin-induced diabetes in rodents reverses neurological and neurovascular deficits when nicotinamide, a weak PARP inhibitor, is administered.

PARP-1 in HIV infection

A critical stage in the life cycle of HIV-1 and other retroviruses is the integration of a DNA duplicate of the viral genome. Growing evidence points to PARP's participation in HIV infection because PARP is necessary for nicking host cell DNA in order for HIV-1 virus DNA to be incorporated [113]. Although the virally encoded integrase is essential for this process, it is also thought that uncharacterized cellular factors play a role in its conclusion. According to reports, DNA damage sensors like PARP-1 are crucial for promoting HIV integration [114] [115]. Independent investigations revealed that nicotinamide, trisubstituted benzamides, and benzopyrone derivatives have strong antiviral effects [116] [117]. Similar findings were also reported by studies that employed chemical, antisense, and dominant negative inhibition as three distinct PARP inhibitory strategies [118].

PARP-1 and Ageing

The phenomenon of ageing is the gradual loss of the body's physical and psychic capacity for environmental adaptation. Recent research showed that the A-T mutated (ATM)-disrupted mice, which was used as an animal model of A-T, age more quickly when PARP-1 is overactive due to DNA damage and chronic neuroinflammation [119]. In accordance with this discovery, PARP-1 inhibitors can enhance senescent cells functionality by raising NAD+ levels and SIRT1 activity. In fact, SIRT1 and NAD+ supplementation through therapy with nicotinamide mononucleotide or nicotinamide riboside, both of which are NAD+ precursors, have anti-aging effects [120] [121] [122] [123].

Clinical, Pre-clinical Studies of PARP inhibitor

PARP-1 inhibitors have undergone comprehensive investigation in both pre-clinical settings, encompassing laboratory and animal investigations, as well as clinical trials involving human participants. The safety, efficacy, and potential applications of PARP-1 inhibitors in many disorders, especially cancer, have been assessed in this research. During the pre-clinical phase, laboratory experiments and animal models were employed to investigate the mechanisms of action, toxicity profiles, and possible therapeutic effects of PARP-1 inhibitors. The primary objective of these research was to prove the proof of concept and offer significant insights into the drug's efficacy against particular forms of cancer, particularly those characterized by defects in DNA repair mechanisms. Preclinical investigations were conducted to assess the anticancer efficacy of PARP-1 inhibitors in cancer cell lines and xenograft models obtained from patient malignancies. These researches have contributed to the identification of malignancies characterized by unique DNA repair pathway abnormalities, which exhibit heightened sensitivity to PARP inhibition. The study involved the implementation of experimental procedures by researchers in order to gain insights into the mechanisms via which PARP-1 inhibitors impede DNA repair processes and trigger synthetic lethality in cancer cells harboring BRCA mutations or other abnormalities in DNA repair mechanisms. Preclinical experiments have also examined the potential of synergizing PARP-1 inhibitors with other cancer treatments, such as chemotherapy or radiation therapy, in order to augment therapeutic effects. Animal toxicology studies were undertaken to assess the safety of PARP-1 inhibitors, ascertain potential adverse effects, and establish suitable dosages for forthcoming clinical trials. The evaluation of safety and efficacy of PARP-1 inhibitors in human patients is carried out through a series of sequential steps in clinical studies. The studies encompass individuals who have been diagnosed with specific forms of cancer, specifically those who possess BRCA mutations or other impairments in the DNA repair pathway. Phase I trials typically comprise a limited cohort of patients and primarily aim to ascertain the appropriate dosage range of the PARP-1 inhibitor, comprehend its pharmacokinetic profile (i. e., absorption, distribution, metabolism, and excretion within the body), and detect any potential adverse effects. Phase II trials aim to augment the patient cohort and conduct more comprehensive investigations into the efficacy of the medication in distinct cancer subtypes. The researchers seek to identify indications of tumor reduction or stability and evaluate the drug's general safety and tolerability. Phase III trials are extensive, randomized investigations that aim to compare the efficacy of the PARP-1 inhibitor with standard treatments or a placebo within well-defined patient populations. The primary objective of these trials is to conclusively show the drug's effectiveness, safety, and possible advantages for patients. If the PARP-1 inhibitor exhibits substantial therapeutic advantages and establishes safety in Phase III trials, it may be eligible for regulatory approval for particular purposes. Post-marketing studies are ongoing to assess the extended safety and efficacy of the medicine in a more diverse patient cohort. In brief, extensive pre-clinical and clinical assessments have been conducted on PARP-1 inhibitors to comprehensively investigate their mechanisms of action, safety characteristics, and therapeutic efficacy, with a specific focus on their application in the field of cancer therapy. The aforementioned investigations have resulted in the authorization of PARP-1 inhibitors for particular cancer indications and continue to propel on-going research endeavours aimed at investigating their potential applications in other medical conditions.

Conclusions

In summary, this review paper has provided insights into the potential advancements of PARP inhibitors in the realm of cancer treatment and other related areas. Several crucial points emerge when considering the assessment of emerging prospects and the customization of therapeutic tactics. PARP drugs have exhibited substantial effectiveness, notably in neoplasms harboring BRCA mutations. The capacity to selectively target DNA repair pathways within malignant cells have resulted in enhanced clinical results and prolonged patient survival. The potential applications of PARP inhibitors extend beyond malignancies associated with BRCA mutations. Recent research findings indicate the potential of utilizing these treatments for a wide range of malignancies and even non-cancerous illnesses characterized by disruptions in DNA repair mechanisms. The utilization of combinatorial strategies, which incorporate PARP inhibitors alongside other targeted medicines, immunotherapies, or conventional treatments, exhibits significant potential in augmenting therapy response and surmounting resistance. The development of biomarkers that can accurately predict the response to PARP inhibitors is of utmost importance in order to effectively identify patients and enhance treatment results. Further investigation in this field is needed in order to enhance the process of categorizing patients based on specific characteristics. The comprehension and effective management of the adverse effects linked to PARP inhibitors are crucial in guaranteeing patient adherence and overall efficacy of treatment. Although PARP inhibitors have demonstrated substantial clinical advantages, the issue of resistance development continues to pose a serious obstacle. A comprehensive examination of resistance mechanisms is important in order to devise efficacious techniques for the mitigation or prevention of resistance. Subsequent investigations should prioritize the exploration of innovative PARP inhibitors, with an emphasis on enhancing their efficacy and specificity, while also delving into their potential when utilized in conjunction with other targeted therapeutic approaches.

Competing Interest

The authors declare that, there is no conflict of interest.

Acknowledgments

Authors expresses their immense gratitude to M.S. Ramaiah University of Applied Sciences, M S R Nagar, Bengaluru-560054, Karnataka, India, Swamy Vivekananda College of Pharmacy, Namakkal, Tamil Nadu, India and Kalasalingam Academy of Research and Education, Krishnankoil, Tamilnadu, India for the facilities offered.

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Publication History

Received: 13 August 2023

Accepted: 18 September 2023

Article published online:
27 October 2023