Document Type
Article
Publication Date
2012
Keywords
Anticancer Drug, Apoptosis, Bcl-2 Family Proteins, Drug Discovery, Drug Resistance, ABT-737, Marinopyrrole A, Maritoclax, Mcl-1, Obatoclax
Digital Object Identifier (DOI)
https://doi.org/10.1074/jbc.M111.334532
Abstract
The anti-apoptotic Bcl-2 family of proteins, including Bcl-2, Bcl-XL and Mcl-1, are well-validated drug targets for cancer treatment. Several small molecules have been designed to interfere with Bcl-2 and its fellow pro-survival family members. While ABT-737 and its orally active analog ABT-263 are the most potent and specific inhibitors to date that bind Bcl-2 and Bcl-XL with high affinity but have a much lower affinity for Mcl-1, they are not very effective as single agents in certain cancer types because of elevated levels of Mcl-1. Accordingly, compounds that specifically target Mcl-1 may overcome this resistance. In this study, we identified and characterized the natural product marinopyrrole A as a novel Mcl-1-specific inhibitor and named it maritoclax. We found that maritoclax binds to Mcl-1, but not Bcl-XL, and is able to disrupt the interaction between Bim and Mcl-1. Moreover, maritoclax induces Mcl-1 degradation via the proteasome system, which is associated with the pro-apoptotic activity of maritoclax. Importantly, maritoclax selectively kills Mcl-1-dependent, but not Bcl-2- or Bcl-XL-dependent, leukemia cells and markedly enhances the efficacy of ABT-737 against hematologic malignancies, including K562, Raji, and multidrug-resistant HL60/VCR, by ∼60- to 2000-fold at 1–2 μm. Taken together, these results suggest that maritoclax represents a new class of Mcl-1 inhibitors, which antagonizes Mcl-1 and overcomes ABT-737 resistance by targeting Mcl-1 for degradation.
Rights Information
This work is licensed under a Creative Commons Attribution 4.0 License.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
Journal of Biological Chemistry, v. 287, issue 12, p. 10224-10235
Scholar Commons Citation
Doi, Kenichiro; Li, Rongshi; Sung, Shen-Shu; Wu, Hongwei; Liu, Yan; Manieri, Wanda; Krishnegowda, Gowdahalli; Awwad, Andy; Dewey, Alden; liu, Xin; Amin, Shantu; Cheng, Chunwei; Qin, Yong; Schonbrunn, Ernst; Daughdrill, Gary W.; Loughran, Thomas P. Jr.; Sebti, Said M.; and Wang, Hong-Gang, "Discovery of Marinopyrrole A (Maritoclax) as a Selective Mcl-1 Antagonist That Overcomes ABT-737 Resistance by Binding to and Targeting Mcl-1 for Proteasomal Degradation*" (2012). Molecular Biosciences Faculty Publications. 149.
https://digitalcommons.usf.edu/bcm_facpub/149
