1. Discovery of novel natural-product-derived mutant isocitrate dehydrogenases 1 inhibitors: Structure-based virtual screening, biological evaluation and structure-activity relationship study.
- Author
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Xu T, Yang J, Li D, Challa M, Zou C, Deng P, Zhang SL, and Xu B
- Subjects
- Humans, Structure-Activity Relationship, Animals, Mice, Molecular Structure, Mutation, Cell Line, Tumor, Drug Evaluation, Preclinical, Neoplasms, Experimental drug therapy, Neoplasms, Experimental pathology, Neoplasms, Experimental metabolism, Isocitrate Dehydrogenase antagonists & inhibitors, Isocitrate Dehydrogenase genetics, Isocitrate Dehydrogenase metabolism, Biological Products pharmacology, Biological Products chemistry, Biological Products chemical synthesis, Enzyme Inhibitors pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors chemical synthesis, Cell Proliferation drug effects, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Drug Discovery, Drug Screening Assays, Antitumor, Dose-Response Relationship, Drug
- Abstract
Mutations in IDH1 are commonly observed across various cancers, causing the conversion of α-KG to 2-HG. Elevated levels of 2-HG disrupt histone and DNA demethylation processes, promoting tumor development. Consequently, there is substantial interest in developing small molecule inhibitors targeting the mutant enzymes. Herein, we report a structure-based high-throughput virtual screening strategy using a natural products library, followed by hit-to-lead optimization. Through this process, we discover a potent compound, named 11s, which exhibited significant inhibition to IDH1 R132H and IDH1 R132C with IC
50 values of 124.4 and 95.7 nM, respectively. Furthermore, 11s effectively reduced 2-HG formation, with EC50 values of 182 nM in U87 R132H cell, and 84 nM in HT-1080 cell. In addition, 11s significantly reduced U87 R132H and HT-1080 cell proliferation with GC50 values of 3.48 and 1.38 μM, respectively. PK-PD experiments further confirmed that compound 11s significantly decreased 2-HG formation in an HT-1080 xenograft mouse model, resulting in notable suppression of tumor growth without apparent loss in body weight., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)- Published
- 2024
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