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

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...