Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL Academic Article uri icon

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.

authors

  • Sleebs, BE
  • Kersten, WJA
  • 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, DCS
  • Colman, PM
  • Street, IP
  • Baell, JB
  • Watson, K
  • Lessene, G

publication date

  • 2013

has subject area