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

• Published in: The Journal of biological chemistry Vol. 287; no. 13; pp. 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: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.03.2012; American Society for Biochemistry and Molecular Biology
• 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; Maritoclax; Mcl-1; Marinopyrrole A; Obatoclax; ABT-737; Drug Discovery; Anticancer Drug; Drug Resistance; Apoptosis; Bcl-2 Family Proteins
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.334532

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.