Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL

Brad Sleebs, Wilhelmus J A Kersten, Sanjitha Kulasegaram, George Nikolakopoulos, Effie Hatzis, Rebecca M Moss, John P Parisot, Hong Yang, Peter Edward Czabotar, W Douglas Fairlie, Erinna F Lee, Jerry M Adams, Lin Chen, Mark F van Delft, Kym N Lowes, Andrew Wei, David CS Huang, Peter M Colman, Ian Philip Street, Jonathan Bayldon BaellKeith Geoffrey Watson, Guillaume Lessene

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43 Citations (Scopus)


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-X-L 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 (M-w <450) and unprecedented selectivity for Bcl-X-L. Surface plasmon resonance experiments afford strong evidence of binding affinity within the hydrophobic groove of Bcl-X-L. Biological experiments using engineered Mcl-1 deficient mouse embryonic fibroblasts (MEFs, reliant only on Bcl-X-L, 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-X-L and provides promising leads for the development of efficacious therapeutics against solid tumors and chemoresistant cancer cell lines.
Original languageEnglish
Pages (from-to)5514 - 5540
Number of pages27
JournalJournal of Medicinal Chemistry
Issue number13
Publication statusPublished - 2013

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