Small-molecule Mcl-1 inhibitors: Emerging anti-tumor agents

Eur J Med Chem. 2018 Feb 25:146:471-482. doi: 10.1016/j.ejmech.2018.01.076.

Yichao Wan ¹, Ningning Dai ¹, Zilong Tang ¹, Hao Fang ²

Affiliations

1 Key Laboratory of Theoretical Organic Chemistry and Functional Molecule, Ministry of Education, Hunan Provincial Key Laboratory of Controllable Preparation and Functional Application of Fine Polymers, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, Hunan 411201, PR China.
2 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmacy, Shandong University, Jinan, Shandong 250012, PR China. Electronic address: haofangcn@sdu.edu.cn.

PMID: 29407973 DOI: 10.1016/j.ejmech.2018.01.076

Abstract

The anti-apoptotic members of B-cell lymphoma-2 (Bcl-2) proteins family, such as Bcl-2 and myeloid cell leukemia-1 (Mcl-1), are the key regulators of the intrinsic pathway of Apoptosis and overexpressed in many tumor cells, which have been confirmed as potential drug targets for cancers. A number of Bcl-2 proteins inhibitors have been developed and conducted clinical trials, but no Mcl-1 inhibitors are presented in the clinics. In addition, Mcl-1 is an important reason for the resistance to radio- and chemotherapies, including inhibitors that target other Bcl-2 Family members. For example, the recently launched Bcl-2-selective inhibitor ABT-199 displays highly potency in the treatment of chronic lymphocytic leukemia (CLL), but it cannot induce the Apoptosis controlled by Mcl-1 in some tumor cell lines. Therefore, developing potent Mcl-1 inhibitors become urgently needed in clinical therapy. This review briefly introduces the structure of Mcl-1 protein, the role in cancers and focuses on the progress of small-molecule Mcl-1 inhibitors from 2012 to 2017.

Keywords

Anti-tumor; Apoptosis; Bcl-2; Inhibitors; Mcl-1.

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