Discovery of Potent and Selective Benzothiazole Hydrazone Inhibitors of Bcl-XL.
Publication Year 2013-07-11,Volume 56,Issue #13,Page 5514-5540
Journal Title
Journal of Medicinal Chemistry
Publication Type
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.
American Chemical Society
WEHI Research Division(s)
Structural Biology; Chemical Biology; Molecular Genetics Of Cancer
NHMRC Grants
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Copyright © 2013 American Chemical Society

Creation Date: 2013-06-26 12:00:00
Last Modified: 2015-03-24 10:21:37
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