Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors

• Type of Material: Article
• Authors: Taekyu Lee, Vanderbilt University; Zhiguo Bian, Vanderbilt University; Bin Zhao, Vanderbilt University; Leah J. Hogdal, Vanderbilt University; John L. Sensintaffar, Vanderbilt University; Craig M. Goodwin, Vanderbilt University; Johannes Belmar, Vanderbilt University; Subrata Shaw, Vanderbilt University; James C. Tarr, Vanderbilt University; Nagarathanam Veerasamy, Vanderbilt University; Shannon M Matulis, Emory University; Brian Koss, St. Jude Children’s Research Hospital; Melissa A. Fischer, Vanderbilt University; Allison L. Arnold, Vanderbilt University; DeMarco V. Camper, Vanderbilt University; Lawrence Boise, Emory University
• Language: English
• Date: 2017-01-01
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Federation of European Biochemical Societies
• Final Published Version (URL): http://dx.doi.org/10.1002/1873-3468.12497
• Title of Journal or Parent Work: FEBS Letters
• ISSN: 0014-5793
• Volume: 591
• Issue: 1
• Start Page: 240
• End Page: 251
• Grant/Funding Information: The Biomolecular NMR Facility at Vanderbilt University is supported in part by a NIH SIG Grant 1S-10RR025677-01 and Vanderbilt University matching funds.; This research was supported by the U.S. National Institutes of Health, NIH Director’s Pioneer Award DP1OD006933/DP1CA174419 to S.W.F., The NCI Experimental Therapeutics (NExT) Program BOA29XS129TO22 under the Leidos Biomed Prime Contract No. HHSN261200800001E, and a career development award to S.W.F. from a NCI SPORE grant in breast cancer (Grant P50CA098131) to C. L. Arteaga.; Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357.
• Keywords: FRAGMENT-BASED METHODS; TARGETING MCL-1; BCL-2; SPECIFICITY; drug discovery; Life Sciences & Biomedicine; apoptosis; cancer; STRUCTURAL-ANALYSIS; HIGH-AFFINITY; Cell Biology; Science & Technology; CANCER-THERAPY; Biochemistry & Molecular Biology; MCL-1 INHIBITORS; PROTEIN; structure-based drug design; STRUCTURE-BASED DESIGN; myeloid cell leukemia 1; Biophysics
• Research Categories: Biology, Molecular; Health Sciences, Oncology

Abstract

Myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that when overexpressed is associated with high tumor grade, poor survival, and resistance to chemotherapy. Mcl-1 is amplified in many human cancers, and knockdown of Mcl-1 using RNAi can lead to apoptosis. Thus, Mcl-1 is a promising cancer target. Here, we describe the discovery of picomolar Mcl-1 inhibitors that cause caspase activation, mitochondrial depolarization, and selective growth inhibition. These compounds represent valuable tools to study the role of Mcl-1 in cancer and serve as useful starting points for the discovery of clinically useful Mcl-1 inhibitors. PDB ID codes: Comp. 2: 5IEZ; Comp. 5: 5IF4.