title: Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL.
abstract: Developing potent molecules that inhibit Bcl-2 family mediated apoptosis affords opportunities to treat cancers via reactivation of the cell death machinery. We describe the hit-to-lead development of selective Bcl-XL inhibitors originating from a high-throughput screening campaign. Small structural changes to the hit compound increased binding affinity more than 300-fold (to IC50 < 20 nM). This molecular series exhibits drug-like characteristics, low molecular weights (Mw < 450), and unprecedented selectivity for Bcl-XL. Surface plasmon resonance experiments afford strong evidence of binding affinity within the hydrophobic groove of Bcl-XL. Biological experiments using engineered Mcl-1 deficient mouse embryonic fibroblasts (MEFs, reliant only on Bcl-XL for survival) and Bax/Bak deficient MEFs (insensitive to selective activation of Bcl-2-driven apoptosis) support a mechanism-based induction of apoptosis. This manuscript describes the first series of selective small-molecule inhibitors of Bcl-XL and provides promising leads for the development of efficacious therapeutics against solid tumors and chemoresistant cancer cell lines.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade, Parkville VIC-3052, Australia.
authors.forename: Brad E
authors.initials: BE
authors.lastname: Sleebs
authors.forename: Wilhemus J A
authors.initials: WJ
authors.lastname: Kersten
authors.forename: Sanji
authors.initials: S
authors.lastname: Kulasegaram
authors.forename: George
authors.initials: G
authors.lastname: Nikolakopoulos
authors.forename: Effie
authors.initials: E
authors.lastname: Hatzis
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Moss
authors.forename: John P
authors.initials: JP
authors.lastname: Parisot
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: Peter E
authors.initials: PE
authors.lastname: Czabotar
authors.forename: W Douglas
authors.initials: WD
authors.lastname: Fairlie
authors.forename: Erinna F
authors.initials: EF
authors.lastname: Lee
authors.forename: Jerry M
authors.initials: JM
authors.lastname: Adams
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Mark F
authors.initials: MF
authors.lastname: van Delft
authors.forename: Kym N
authors.initials: KN
authors.lastname: Lowes
authors.forename: Andrew
authors.initials: A
authors.lastname: Wei
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.forename: Peter M
authors.initials: PM
authors.lastname: Colman
authors.forename: Ian P
authors.initials: IP
authors.lastname: Street
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Baell
authors.forename: Keith
authors.initials: K
authors.lastname: Watson
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lessene
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D055808:Drug Discovery; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006835:Hydrazones / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D008956:Models, Chemical; D015394:Molecular Structure; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000172:deficiency / Q000235:genetics; D020349:Surface Plasmon Resonance; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000172:deficiency / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000235:genetics; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D052160:Benzothiazoles; D006835:Hydrazones; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C005465:benzothiazole