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

• Published in: European journal of medicinal chemistry 2015-01, Vol.90, p.315-331
• Main Authors: Li, Rongshi, Cheng, Chunwei, Balasis, Maria E., Liu, Yan, Garner, Thomas P., Daniel, Kenyon G., Li, Jerry, Qin, Yong, Gavathiotis, Evripidis, Sebti, Said M.
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis Regulatory Proteins - metabolism; bcl-X Protein - antagonists & inhibitors; bcl-X Protein - metabolism; Binding Sites - drug effects; Dose-Response Relationship, Drug; Drug Design; Humans; Marinopyrroles; Mcl-1 and Bcl-xL antagonists; Molecular Structure; Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Protein–protein interaction; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.11.035

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. [Display omitted] •Synthesis of novel marinopyrrole derivatives.•Identified marinopyrroles as selective Mcl-1 or dual Mcl-1/Bcl-xL inhibitors.•Structure activity relationships of novel marinopyrroles bound to Mcl-1.•Marinopyrroles bind to the Mcl-1 BH3 pocket.•Marinopyrroles downregulate Mcl-1 levels and induce apoptosis.