title: 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.
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.
authors.affiliation: Department of Pharmaceutical Sciences, Center for Drug Discovery, College of Pharmacy, Cancer Genes and Molecular Regulation Program, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198, United States.|Department of Drug Discovery, Chemical Biology & Molecular Medicine Program, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, United States.|Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs, Tampa, FL 33612, United States.
authors.forename: Rongshi
authors.initials: R
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems of the Ministry of Education, West China School of Pharmacy, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China.
authors.forename: Chunwei
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Drug Discovery, Chemical Biology & Molecular Medicine Program, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, United States.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Balasis
authors.affiliation: Department of Pharmaceutical Sciences, Center for Drug Discovery, College of Pharmacy, Cancer Genes and Molecular Regulation Program, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Departments of Biochemistry and Medicine, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Jack and Pearl Resnick Campus, 1300 Morris Park Avenue, Forchheimer G46, Bronx, NY 10461, United States.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Garner
authors.affiliation: Department of Drug Discovery, Chemical Biology & Molecular Medicine Program, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, United States.
authors.forename: Kenyon G
authors.initials: KG
authors.lastname: Daniel
authors.affiliation: Department of Drug Discovery, Chemical Biology & Molecular Medicine Program, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, United States.
authors.forename: Jerry
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems of the Ministry of Education, West China School of Pharmacy, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Departments of Biochemistry and Medicine, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Jack and Pearl Resnick Campus, 1300 Morris Park Avenue, Forchheimer G46, Bronx, NY 10461, United States.
authors.forename: Evripidis
authors.initials: E
authors.lastname: Gavathiotis
authors.affiliation: Department of Drug Discovery, Chemical Biology & Molecular Medicine Program, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, United States.|Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs, Tampa, FL 33612, United States.
authors.forename: Said M
authors.initials: SM
authors.lastname: Sebti
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011758:Pyrroles; D051020:bcl-X Protein; C528298:marinopyrrole A
keywords: Apoptosis; Marinopyrroles; Mcl-1 and Bcl-xL antagonists; Protein–protein interaction