2. Academic Validation
  3. Discovery of Novel Benzothiazepinones as Irreversible Covalent Glycogen Synthase Kinase 3β Inhibitors for the Treatment of Acute Promyelocytic Leukemia

Discovery of Novel Benzothiazepinones as Irreversible Covalent Glycogen Synthase Kinase 3β Inhibitors for the Treatment of Acute Promyelocytic Leukemia

  • J Med Chem. 2021 Jun 10;64(11):7341-7358. doi: 10.1021/acs.jmedchem.0c02254.
Peng Zhang 1 2,  Zhihui Min 3,  Yang Gao 1,  Jiang Bian 1,  Xin Lin 1,  Jie He 1,  Deyong Ye 1,  Yilin Li 4,  Chao Peng 4,  Yunfeng Cheng 3,  Yong Chu 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 2 State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of Anti-Infectives, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 201203, China.
  • 3 Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 4 National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai 201210, China.
PMID: 34027661 DOI: 10.1021/acs.jmedchem.0c02254
Abstract

Recently, irreversible inhibitors have attracted great interest in antitumors due to their advantages of forming covalent bonds to target proteins. Herein, some benzothiazepinone compounds (BTZs) have been designed and synthesized as novel covalent GSK-3β inhibitors with high selectivity for the kinase panel. The irreversible covalent binding mode was identified by kinetics and mass spectrometry, and the main labeled residue was confirmed to be the unique Cys14 that exists only in GSK-3β. The candidate 4-3 (IC50 = 6.6 μM) showed good proliferation inhibition and apoptosis-inducing ability to leukemia cell lines, low cytotoxicity on normal cell lines, and no hERG inhibition, which hinted the potential efficacy and safety. Furthermore, 4-3 exhibited decent pharmacokinetic properties in vivo and remarkably inhibited tumor growth in the acute promyelocytic leukemia (APL) mouse model. All the results suggest that these newly irreversible BTZ compounds might be useful in the treatment of Cancer such as APL.

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