Discovery of Potent and Selective Benzothiazole Hydrazone Inhibitors of Bcl-XL.
- Sleebs, BE; Kersten, WJ; Kulasegaram, S; Nikolakopoulos, G; Hatzis, E; Moss, RM; Parisot, JP; Yang, H; Czabotar, PE; Fairlie, WD; Lee, EF; Adams, JM; Chen, L; van Delft, MF; Lowes, KN; Wei, A; Huang, DC; Colman, PM; Street, IP; Baell, JB; Watson, K; Lessene, G;
Publication Year 2013-07-11, Volume 56, Issue #13, Page 5514-5540
- Journal Title
- Journal of Medicinal Chemistry
- Publication Type
- JOURNAL ARTICLE
- 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
- Publisher's Version
- Rights Notice
- Copyright © 2013 American Chemical Society
Creation Date: 2013-06-26 12:00:00Last Modified: 2015-03-24 10:21:37