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  3. Discovery of novel natural-product-derived mutant isocitrate dehydrogenases 1 inhibitors: Structure-based virtual screening, biological evaluation and structure-activity relationship study

Discovery of novel natural-product-derived mutant isocitrate dehydrogenases 1 inhibitors: Structure-based virtual screening, biological evaluation and structure-activity relationship study

  • Eur J Med Chem. 2024 Jun 17:275:116610. doi: 10.1016/j.ejmech.2024.116610.
Tieling Xu 1,  Junya Yang 1,  Dongsheng Li 1,  Mahesh Challa 2,  Cheng Zou 2,  Ping Deng 3,  Shao-Lin Zhang 4,  Biao Xu 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China.
  • 2 School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing, 401331, PR China.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China. Electronic address: 100865@cqmu.ed.cn.
  • 4 School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing, 401331, PR China. Electronic address: zhangsl@cqu.edu.cn.
  • 5 Department of Medicinal Chemistry, School of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China. Electronic address: xubiao@cqmu.edu.cn.
PMID: 38896992 DOI: 10.1016/j.ejmech.2024.116610
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 IC50 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.

Keywords

Anticancer; Cancer metabolism; Isocitrate dehydrogenases 1; Structure-based virtual screening.

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