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Planta Med 2020; 86(07): 482-488
DOI: 10.1055/a-1125-0385
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Determining the Drug-Like Properties of Ailanthone, a Novel Chinese Medicine Monomer with Anti-CRPC Activity

Pan Hu
1   Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
,
Dandan Guo
1   Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
,
Jiayi Xie
1   Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
,
Huang Chen
1   Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
,
Shixiu Hu
2   Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, China
,
Aiwu Bian
1   Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
,
Shifen Xu
3   Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
,
Zhengfang Yi
1   Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
4   Joint Research Center for Translational Medicine, East China Normal University and Shanghai Fengxian District Central Hospital, Shanghai, China
,
Shihong Peng
1   Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
,
Mingyao Liu
1   Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
4   Joint Research Center for Translational Medicine, East China Normal University and Shanghai Fengxian District Central Hospital, Shanghai, China
› Author AffiliationsSupported by: Science and Technology Commission of Shanghai Municipality 11DZ2260300
Supported by: Major State Basic Research Development Program of China 2018YFA0507001
Supported by: China Postdoctoral Science Foundation 2018M632065
Supported by: Innovation program of Shanghai municipal education commission 2017-01-07-00-05-E00011
Supported by: the Fundamental Research Funds for the Central Universities
Supported by: ECNU Public Platform for innovation 011
Supported by: Shenzhen Municipal Government of China KQTD20170810160226082
Supported by: National Natural Science Foundation of China 81773204, 81472788, 81830083, 81802970
Further Information

Publication History

received 24 September 2019
revised 10 February 2020

accepted 18 February 2020

Publication Date:
13 March 2020 (online)

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Abstract

Approximately 40% of compounds with therapeutic potential cannot be successfully developed into drugs owing to their poor pharmaceutical properties, emphasising the need to profile their drug-like properties as early as possible during preclinical development. This study aimed to evaluate the drug-like properties of ailanthone, a novel Chinese medicine monomer that was shown to have activity against castration-resistant prostate cancer tumour growth and metastasis in our previous study. The drug-like properties detected in the present study included effects on permeability, liver microsome stability, plasma protein binding rate, plasma stability, and human ether-à-go-go-related gene inhibition. Additionally, the following results were obtained: the efflux ratio of ailanthone was > 32 during permeability detection; the half-life and intrinsic clearance (Clint) in mouse, rat, and human liver microsomes were > 145 min and < 9.6 µL/min/mg protein, respectively. The Clint(liver) of ailanthone was < 38.0, < 17.3, and < 8.6 mL/min/kg body weight in mice, rats, and humans, respectively. The plasma protein binding percentage of ailanthone was 16.6 ± 4.2% in human plasma, with 62.5% remaining at 120 min after incubation. The IC50 value of ailanthone for the human ether-à-go-go-related gene channels was > 30 µM. Collectively, these results and those from our previous study indicate that the pharmacokinetic properties of ailanthone are suitable for the potential development of this compound as an oral or intravenous drug for the treatment of castration-resistant prostate cancer.

Key words

AIL - Simaroubaceae - drug-like properties - LC-MS/MS
 

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