title: Fragment-based discovery of potent inhibitors of the anti-apoptotic MCL-1 protein.
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.
authors.affiliation: Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States. Electronic address: andrew.petros@abbvie.com.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Petros
authors.affiliation: Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Swann
authors.affiliation: Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States.
authors.forename: Danying
authors.initials: D
authors.lastname: Song
authors.affiliation: Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States.
authors.forename: Kerren
authors.initials: K
authors.lastname: Swinger
authors.affiliation: Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States.
authors.forename: Chang
authors.initials: C
authors.lastname: Park
authors.affiliation: Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States.
authors.forename: Haichao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wendt
authors.affiliation: Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Kunzer
authors.affiliation: Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Souers
authors.affiliation: Research & Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, United States. Electronic address: chaohong.sun@abbvie.com.
authors.forename: Chaohong
authors.initials: C
authors.lastname: Sun
mesh_terms: D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020156:Salicylic Acid / Q000737:chemistry / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism
chemical_list: D001713:Biphenyl Compounds; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D020156:Salicylic Acid; D013449:Sulfonamides; C010574:biphenyl
keywords: Apoptosis; BCL; FBDD; FBLD; Fragment-based; MCL-1; NMR