1445800-21-4Relevant articles and documents
Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL
Sleebs, Brad E.,Kersten, Wilhemus J. A.,Kulasegaram, Sanji,Nikolakopoulos, George,Hatzis, Effie,Moss, Rebecca M.,Parisot, John P.,Yang, Hong,Czabotar, Peter E.,Fairlie, W. Douglas,Lee, Erinna F.,Adams, Jerry M.,Chen, Lin,Van Delft, Mark F.,Lowes, Kym N.,Wei, Andrew,Huang, David C.S.,Colman, Peter M.,Street, Ian P.,Baell, Jonathan B.,Watson, Keith,Lessene, Guillaume
, p. 5514 - 5540 (2013/07/26)
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 w L. 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.
