Details
The BH4 domain of Bcl2 is required for its antiapoptotic function, thus constituting a promising anticancer
target. We identified a small-molecule Bcl2-BH4 domain antagonist, BDA-366, that binds BH4 with high
affinity and selectivity. BDA-366-Bcl2 binding induces conformational change in Bcl2 that abrogates its antiapoptotic
function, converting it from a survival molecule to a cell death inducer. BDA-366 suppresses
growth of lung cancer xenografts derived from cell lines and patient without significant normal tissue toxicity
at effective doses. mTOR inhibition upregulates Bcl2 in lung cancer cells and tumor tissues from clinical trial
patients. Combined BDA-366 and RAD001 treatment exhibits strong synergy against lung cancer in vivo.
Development of this Bcl2-BH4 antagonist may provide a strategy to improve lung cancer outcome.
China (Mainland)