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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Recent Advances in Cancer Drug Development: Targeting Induced Myeloid Cell Leukemia-1 (Mcl-1) Differentiation Protein

Author(s): Mohammad Abid*, Yogesh A. Sonawane, Jacob I. Contreras, Sandeep Rana and Amarnath Natarajan*

Volume 24 , Issue 40 , 2017

Page: [4488 - 4514] Pages: 27

DOI: 10.2174/0929867324666170912092659

Price: $65

Abstract

Background: Anti-apoptotic members of the Bcl-2 family of proteins are upregulated in a majority of cancers and are potential therapeutic targets. Fragment-based design led to the development of clinical candidates that target Bcl-xL/Bcl-2. Although these BclxL/ Bcl-2 inhibitors showed promise in pre-clinical studies, resistance to several Bcl-xL inhibitors was observed, when used alone. This is attributed to the over-expression of Mcl-1, another member of the Bcl-2 family of proteins. Indeed, Mcl-1 is highly amplified in numerous cancers, suggesting that it may contribute to malignant cell growth and evasion of apoptosis. Therefore, significant efforts have been made toward the development of direct Mcl-1 inhibitors for cancer therapy.

Methods: Following an extensive search of peer-reviewed articles on the development of Mcl-1-selective inhibitors, the literature retrieved is chronologically arranged and discussed in this review article.

Results: We have included 147 articles in this review; including articles that describe the development of stapled peptides with improved binding affinity as Mcl-1-selective BH3 mimetics, those describing fragment-based and structure-based design of small molecule Mcl-1 inhibitors by various research groups, and those detailing the use of natural products and their derivatives as potential Mcl-1 inhibitors.

Conclusion: The therapeutic potential of targeting the Mcl-1 protein for cancer drug discovery is vast. Stapling BH3 peptides, as well as the development of small molecule inhibitors as BH3 mimetics, are viable strategies to develop selective Mcl-1 inhibitors. With no clinically approved candidate in hand, additional modes of perturbing the biological function of this protein will aid drug discovery efforts.

Keywords: Cancer, apoptosis, Mcl-1, Bcl-2, Bcl-xL, BH3-mimetics, small molecule inhibitors.


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