Discovery of potent and selective Bcl-2 inhibitors with acyl sulfonamide skeleton

  • Bioorg Med Chem. 2021 Oct 1:47:116350. doi: 10.1016/j.bmc.2021.116350.
Bin Wang  1 ,  Weiwei Feng  2 ,  Jinan Wang  2 ,  Yuanzhen Dong  3 ,  Yanlong Liu  2 ,  Yiyan Yao  2 ,  Jianqing Zhang  2 ,  Wei Shi  2 ,  Limin Liu  2 ,  Hongying Zhang  2 ,  Xiangyi He  2 ,  Xiayun Chang  2 ,  Xiaojin Wang  2 ,  Hongjiang Xu  2 ,  Fei Liu  4 ,  Jun Feng  5
Affiliations
  • 1. State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 201203 Shanghai, China; R&D Institute, Chia Tai Tianqing Pharmaceutical Group Co., Ltd, 1099 Fuying Road, Jiangning District, Nanjing, Jiangsu Province, China.
  • 2. R&D Institute, Chia Tai Tianqing Pharmaceutical Group Co., Ltd, 1099 Fuying Road, Jiangning District, Nanjing, Jiangsu Province, China.
  • 3. State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 201203 Shanghai, China.
  • 4. R&D Institute, Chia Tai Tianqing Pharmaceutical Group Co., Ltd, 1099 Fuying Road, Jiangning District, Nanjing, Jiangsu Province, China. Electronic address: [email protected].
  • 5. State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 201203 Shanghai, China. Electronic address: [email protected].
PMID: 34536651 DOI: 10.1016/j.bmc.2021.116350
Abstract

The antiapoptotic protein B-cell lymphoma 2 (Bcl-2), overexpressed in many tumor cells, is an attractive target for potential small molecule Anticancer drug discovery. Herein, a series of novel derivatives with acyl sulfonamide skeleton was designed, synthesized, and evaluated as Bcl-2 inhibitors by means of bioisosteric replacement. Among them, compound 24g demonstrated equal efficient inhibition activity against RS4;11 cell line compared to positive control ABT-199. Moreover, it showed improved selectivity for Bcl-2/Bcl-xL inhibitory effects, the result of which was consistent with platelet toxicity studies. In vitro and in vivo pharmacokinetic properties of compound 24g had a significantly improved profiles. Taken together, those results suggested it as a promising candidate for development of novel therapeutics targeting Bcl-2 in Cancer.

Keywords
Acyl sulfonamide; Apoptosis; Bcl-2 inhibitors; Metabolic stability; Selectivity.