Design, Synthesis, and Evaluation of Phenylpyrrole Derivatives as Small-Molecule Activators of BAX

Small-molecule BAX activators can trigger intrinsic apoptosis
directly
and thus hold unique potential as a new class of anticancer therapy.
Current arsenal of known BAX activators is very limited. In this work,
we first identified an active hit with micromolar binding affinity
to BAX through virtual screening, and then replaced the complex hexahydrocyclopenta[c]quinoline moiety in its structure through scaffold hopping.
Multiple rounds of structural optimization led us to finally focus
on the compounds with a phenylpyrrole core moiety. The optimal compound
(27c) exhibited selective binding to BAX with submicromolar
binding affinity (IC50 = 300 nmol/L).
Functional assays validated that 27c activated BAX in
living cells and consequently induced intrinsic apoptosis. Cell viability
tests indicated that 27c was effective not only against
hematologic cancers but also drug-resistant solid tumors when combined
with a BCL-XL inhibitor. Although the in vivo PK properties of 27c revealed certain limitations such
as relatively short half-life and rapid clearance, its novel structural
scaffold and compelling in vitro potency position
it as a promising starting point for future development.