Abstract
Background Endoplasmic Reticulum (ER) stress and Unfolded Protein Response
(UPR) play a key role in cancer progression. The aggregation of incorrectly
folded proteins in the ER generates ER stress, which in turn activates the UPR
as an adaptive mechanism to fix ER proteostasis. Inositol-requiring enzyme 1
(IRE1) is the most evolutionary conserved ER stress sensor, which plays a
pro-tumoral role in various cancers. Targeting its’ active sites is one
of the most practical approaches for the treatment of cancers.
Objective In this study, we aimed to use the structure of 4μ8C as
a template to produce newly designed compounds as IRE1 inhibitors.
Methods Various functional groups were added to the 4μ8C, and
their binding affinity to the target sites was assessed by conducting a covalent
molecular docking study. The potential of the designed compound for further in
vitro and in vivo studies was evaluated using ADMET analysis.
Results Based on the obtained results, the addition of hydroxyl groups to
4μ8C enhanced the binding affinity of the designed compound to the
target efficiently. Compound 17, which was constructed by the addition of one
hydroxyl group to the structure of 4μ8C, can construct a strong covalent
bond with Lys907. The outcomes of ADMET analysis indicated that compound 17
could be considered a drug-like molecule.
Conclusion Our results revealed that designed compound 17 could inhibit
IRE1 activity. Therefore, this designed compound is a remarkable inhibitor of
IRE1 and introduces a promising therapeutic strategy for cancer treatment.
Key words
cancer - UPR response - IRE1 - 4μ8C - molecular docking - In-silico methods
