Design, synthesis and evaluation of marinopyrrole derivatives as selective inhibitors of Mcl-1 binding to pro-apoptotic Bim and dual Mcl-1/Bcl-xL inhibitors

Rongshi Li, Chunwei Cheng, Maria E. Balasis, Yan Liu, Thomas P. Garner, Kenyon G. Daniel, Jerry Li, Yong Qin, Evripidis Gavathiotis, Said M. Sebti

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Inhibition of anti-apoptotic Mcl-1 is a promising anticancer strategy to overcome the survival and chemoresistance of a broad spectrum of human cancers. We previously reported on the identification of a natural product marinopyrrole A (1) that induces apoptosis in Mcl-1-dependent cells through Mcl-1 degradation. Here, we report the design and synthesis of novel marinopyrrole-based analogs and their evaluation as selective inhibitors of Mcl-1 as well as dual Mcl-1/Bcl-xL inhibitors. The most selective Mcl-1 antagonists were 34, 36 and 37 with 16-, 13-and 9-fold more selectivity for disrupting Mcl-1/Bim over Bcl-xL/Bim binding, respectively. Among the most potent dual inhibitors is 42 which inhibited Mcl-1/Bim and Bcl-xL/Bim binding 15-fold (IC50 = 600 nM) and 33-fold (500 nM) more potently than (±)-marinopyrrole A (1), respectively. Fluorescence quenching, NMR analysis and molecular docking indicated binding of marinopyrroles to the BH3 binding site of Mcl-1. Several marinopyrroles potently decreased Mcl-1 cellular levels and induced caspase 3 activation in human breast cancer cells. Our studies provide novel "lead" marinopyrroles for further optimization as selective Mcl-1 inhibitors and dual Mcl-1 and Bcl-xL inhibitors.

Original languageEnglish (US)
Pages (from-to)315-331
Number of pages17
JournalEuropean Journal of Medicinal Chemistry
Volume90
DOIs
StatePublished - 2014

Fingerprint

Molecular Docking Simulation
Derivatives
Biological Products
Caspase 3
Inhibitory Concentration 50
Quenching
Fluorescence
Chemical activation
Binding Sites
Cells
Nuclear magnetic resonance
Apoptosis
Breast Neoplasms
Degradation
Survival
Neoplasms
marinopyrrole A
Lead

Keywords

  • Apoptosis
  • Marinopyrroles
  • Mcl-1 and Bcl-xL antagonists
  • Proteineprotein interaction

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Design, synthesis and evaluation of marinopyrrole derivatives as selective inhibitors of Mcl-1 binding to pro-apoptotic Bim and dual Mcl-1/Bcl-xL inhibitors. / Li, Rongshi; Cheng, Chunwei; Balasis, Maria E.; Liu, Yan; Garner, Thomas P.; Daniel, Kenyon G.; Li, Jerry; Qin, Yong; Gavathiotis, Evripidis; Sebti, Said M.

In: European Journal of Medicinal Chemistry, Vol. 90, 2014, p. 315-331.

Research output: Contribution to journalArticle

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AU - Li, Rongshi

AU - Cheng, Chunwei

AU - Balasis, Maria E.

AU - Liu, Yan

AU - Garner, Thomas P.

AU - Daniel, Kenyon G.

AU - Li, Jerry

AU - Qin, Yong

AU - Gavathiotis, Evripidis

AU - Sebti, Said M.

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AB - Inhibition of anti-apoptotic Mcl-1 is a promising anticancer strategy to overcome the survival and chemoresistance of a broad spectrum of human cancers. We previously reported on the identification of a natural product marinopyrrole A (1) that induces apoptosis in Mcl-1-dependent cells through Mcl-1 degradation. Here, we report the design and synthesis of novel marinopyrrole-based analogs and their evaluation as selective inhibitors of Mcl-1 as well as dual Mcl-1/Bcl-xL inhibitors. The most selective Mcl-1 antagonists were 34, 36 and 37 with 16-, 13-and 9-fold more selectivity for disrupting Mcl-1/Bim over Bcl-xL/Bim binding, respectively. Among the most potent dual inhibitors is 42 which inhibited Mcl-1/Bim and Bcl-xL/Bim binding 15-fold (IC50 = 600 nM) and 33-fold (500 nM) more potently than (±)-marinopyrrole A (1), respectively. Fluorescence quenching, NMR analysis and molecular docking indicated binding of marinopyrroles to the BH3 binding site of Mcl-1. Several marinopyrroles potently decreased Mcl-1 cellular levels and induced caspase 3 activation in human breast cancer cells. Our studies provide novel "lead" marinopyrroles for further optimization as selective Mcl-1 inhibitors and dual Mcl-1 and Bcl-xL inhibitors.

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