2. Academic Validation
  3. Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL

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

  • J Med Chem. 2013 Jul 11;56(13):5514-40. doi: 10.1021/jm400556w.
Brad E Sleebs 1,  Wilhemus J A Kersten,  Sanji Kulasegaram,  George Nikolakopoulos,  Effie Hatzis,  Rebecca M Moss,  John P Parisot,  Hong Yang,  Peter E Czabotar,  W Douglas Fairlie,  Erinna F Lee,  Jerry M Adams,  Lin Chen,  Mark F van Delft,  Kym N Lowes,  Andrew Wei,  David C S Huang,  Peter M Colman,  Ian P Street,  Jonathan B Baell,  Keith Watson,  Guillaume Lessene
Affiliations

Affiliation

  • 1 The Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade, Parkville VIC-3052, Australia.
PMID: 23767404 DOI: 10.1021/jm400556w
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.

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