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

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...

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Published in:The Journal of biological chemistry 2012-03, Vol.287 (13), p.10224-10235
Main Authors: 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, Loughran, Thomas P., Sebti, Said, Wang, Hong-Gang
Format: Article
Language:English
Subjects:
ABT-737
Animals
Anticancer Drug
Apoptosis
Bcl-2 Family Proteins
bcl-X Protein - antagonists & inhibitors
bcl-X Protein - genetics
bcl-X Protein - metabolism
Biphenyl Compounds - pharmacology
Cell Biology
Drug Discovery
Drug Resistance
Drug Resistance, Neoplasm - drug effects
Drug Resistance, Neoplasm - genetics
HL-60 Cells
Humans
Jurkat Cells
K562 Cells
Leukemia - drug therapy
Leukemia - genetics
Leukemia - metabolism
Marinopyrrole A
Maritoclax
Mcl-1
Mice
Myeloid Cell Leukemia Sequence 1 Protein
Nitrophenols - pharmacology
Obatoclax
Piperazines - pharmacology
Proteasome Endopeptidase Complex - metabolism
Proteolysis - drug effects
Proto-Oncogene Proteins c-bcl-2 - genetics
Proto-Oncogene Proteins c-bcl-2 - metabolism
Pyrroles
Sulfonamides - pharmacology
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Summary: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. There is an urgent need to develop small molecule Mcl-1-specific inhibitors for the treatment of Mcl-1-dependent ABT-737/263-resistant cancers. Maritoclax binds to and induces Mcl-1 degradation, thereby leading to Mcl-1-dependent apoptosis and sensitizing leukemia/lymphoma cells to ABT-737. Maritoclax is a novel Mcl-1-specific inhibitor. Antagonizing Mcl-1 by maritoclax has the potential to prevent and overcome Mcl-1-mediated resistance to ABT-737/263.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M111.334532