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J Med Chem. 2013 Jul 11;56(13):5514-40. doi: 10.1021/jm400556w. Epub 2013 Jun 26.

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

Author information

1
The Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade, Parkville VIC-3052, Australia.

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.

PMID:
23767404
DOI:
10.1021/jm400556w
[Indexed for MEDLINE]

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