2. Academic Validation
  3. Discovery of 4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxamide derivatives as PI3Kα inhibitors via virtual screening and docking-based structure optimization

Discovery of 4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxamide derivatives as PI3Kα inhibitors via virtual screening and docking-based structure optimization

  • Bioorg Med Chem. 2023 May 15:86:117288. doi: 10.1016/j.bmc.2023.117288.
Dongyan Gu 1,  Mengmeng Zhang 2,  Lvtao Cai 1,  Chang Wang 2,  Yu-Bo Zhou 3,  Jia Li 4,  Rong Sheng 5
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.
  • 2 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: ybzhou@simm.ac.cn.
  • 4 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: jli@simm.ac.cn.
  • 5 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China. Electronic address: shengr@zju.edu.cn.
PMID: 37126967 DOI: 10.1016/j.bmc.2023.117288
Abstract

Compound 1 with pyrazolo[1,5-a]quinoxalin-4(5H)-one scaffold was identified as a PI3Kα Inhibitor hit via virtual screening strategy. Additional similarity search and molecular docking based structural modification yielded a novel series of pyrazolo[1,5-a]quinoxalin-4(5H)-one derivatives. The most potent compound 49b exhibited remarkably improved PI3Kα inhibitory activity with IC50 value of 0.24 μM and moderate to good isoform selectivity over Other class I PI3K isoforms. In addition, 49b significantly inhibited the proliferation of Kasumi-1 and T47D cells with IC50 value of 1.64 and 1.82 μM, respectively. Further PK study demonstrated that it has favorable pharmacokinetic profiles (AUC0-t = 3294.05 ng·h/mL at 5.0 mg/kg PO, F = 91.8%). All these data indicated that compound 49b was a promising PI3Kα Inhibitor with beneficial drug-like properties and merited further development.

Keywords

PI3Kα inhibitors; Structure optimization; Virtual screening.

Figures