2. Academic Validation
  3. Discovery of potent and selective Bcl-2 inhibitors with acyl sulfonamide skeleton

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

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: LIUFEI@CTTQ.com.
  • 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: Fengjdmr@163.com.
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.

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