Fragment-based discovery of potent inhibitors of the anti-apoptotic MCL-1 protein |
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| Institution: | 1. Clemens Schöpf—Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt, 64287 Darmstadt, Hessen, Germany;2. KU Leuven, Laboratory for Neurobiology and Gene Therapy, Leuven B-3000, Belgium;1. Mercachem, PO Box 6747, 6503 GE Nijmegen, The Netherlands;2. Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute of Molecules, Medicines & Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands;3. Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Groenenborgerlaan 171, 2020 Wilrijk, Belgium;4. DNDi (Drugs for Neglected Diseases initiative), 15 Chemin Louis Dunant, 1202 Geneva, Switzerland;5. Takeda, Takeda Pharmaceuticals International GmbH, Thurgauerstrasse 130, 8152 Glattpark-Opfikon, Zurich, Switzerland;6. Institute of Cell Biology, University of Bern, Baltzerstrasse 4, 3012 Bern, Switzerland;1. Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Glen Hospital, 1001 Decarie Blvd, Montreal H4A 3J1, Quebec, Canada;2. Chemical Computing Group Inc., 1010 Sherbrooke Street West, Suite 910, Montreal H3A 2R7, Quebec, Canada;1. School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China;2. School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China;3. School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China;4. Department of Medicinal Chemistry, University of Florida, 1345 Center Drive, Gainesville, FL 32610, USA;1. Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA;2. School of Chemistry, University of Cardiff, CF10 3AT, UK;3. Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 22 S. Greene St., Baltimore, MD 21201, USA;4. Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA;5. PharmD Program, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA;6. Bryn Mawr School, 109 W. Melrose Ave., Baltimore, MD 21210, USA;7. University of Maryland Greenebaum Cancer Center, 22 S. Greene St., Baltimore, MD 21201, USA |
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| Abstract: | Apoptosis is regulated by the BCL-2 family of proteins, which is comprised of both pro-death and pro-survival members. Evasion of apoptosis is a hallmark of malignant cells. One way in which cancer cells achieve this evasion is thru overexpression of the pro-survival members of the BCL-2 family. Overexpression of MCL-1, a pro-survival protein, has been shown to be a resistance factor for Navitoclax, a potent inhibitor of BCL-2 and BCL-XL. Here we describe the use of fragment screening methods and structural biology to drive the discovery of novel MCL-1 inhibitors from two distinct structural classes. Specifically, cores derived from a biphenyl sulfonamide and salicylic acid were uncovered in an NMR-based fragment screen and elaborated using high throughput analog synthesis. This culminated in the discovery of selective and potent inhibitors of MCL-1 that may serve as promising leads for medicinal chemistry optimization efforts. |
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| Keywords: | NMR Fragment-based FBDD FBLD Apoptosis BCL MCL-1 |
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