1 research outputs found
Discovery of Potent and Selective Benzothiazole Hydrazone Inhibitors of Bcl‑X<sub>L</sub>
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<sub>L</sub> inhibitors originating from a high-throughput
screening campaign. Small structural changes to the hit compound increased
binding affinity more than 300-fold (to IC<sub>50</sub> < 20 nM).
This molecular series exhibits drug-like characteristics, low molecular
weights (<i>M</i><sub>w</sub> < 450), and unprecedented
selectivity for Bcl-X<sub>L</sub>. Surface plasmon resonance experiments
afford strong evidence of binding affinity within the hydrophobic
groove of Bcl-X<sub>L</sub>. Biological experiments using engineered
Mcl-1 deficient mouse embryonic fibroblasts (MEFs, reliant only on
Bcl-X<sub>L</sub> 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<sub>L</sub> and provides
promising leads for the development of efficacious therapeutics against
solid tumors and chemoresistant cancer cell lines