Recent advances in cancer drug development: Targeting induced myeloid cell leukemia-1 (mcl-1) differentiation protein

Mohammad Abid, Yogesh A. Sonawane, Jacob I. Contreras, Sandeep Rana, Amarnath Natarajan

Research output: Contribution to journalReview article

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4488-4514
Number of pages27
JournalCurrent medicinal chemistry
Volume24
Issue number40
DOIs
Publication statusPublished - Jan 1 2017

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Keywords

  • Apoptosis
  • BH3-mimetics
  • Bcl-2
  • Bcl-xL
  • Cancer
  • Mcl-1
  • Small molecule inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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