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  3. Design, synthesis and biological evaluation of dual Bcl-2/Mcl-1 inhibitors bearing 2-(1H-indol-4-yl)benzoic acid scaffold

Design, synthesis and biological evaluation of dual Bcl-2/Mcl-1 inhibitors bearing 2-(1H-indol-4-yl)benzoic acid scaffold

  • Bioorg Med Chem Lett. 2021 Sep 1;47:128215. doi: 10.1016/j.bmcl.2021.128215.
Qun Niu 1,  Hongguang Deng 1,  Zhenwei Zhang 1,  Qinhao Xu 1,  Shenglin Luan 2,  Min Huang 1,  Dan Liu 1,  Linxiang Zhao 3
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2 Shenzhen Bay Laboratory, Shenzhen, China.
  • 3 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: [email protected].
PMID: 34153472 DOI: 10.1016/j.bmcl.2021.128215
Abstract

The anti-apoptotic protein inhibitors of the B cell lymphoma 2 (Bcl-2) family have been developed as new Anticancer therapies. Numerous studies illustrated the great potential in the development of dual Bcl-2/myeloid cell leukemia 1 (Mcl-1) inhibitors. Herein, we reported a series of Bcl-2/Mcl-1 inhibitors that optimized from a hit compound 1 via structure-based rational design. The biological evaluation suggested that most compounds exhibited potent binding affinities at submicromolar to both Bcl-2 and Mcl-1 without any Bcl-xL binding affinities, especially compound 9o, with a Ki value of 0.07 μM to Mcl-1 and 0.66 μM to Bcl-2, that has great potential for developing dual inhibitors targeting Bcl-2 and Mcl-1.

Keywords

Bcl-2/Mcl-1; Dual inhibitor; Structure-based rational design.

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