BDA-366 is a selective antagonist of BCL2 BH4 domain with Ki value of 3.3 nM [1].
BCL2 is an important anti-apoptotic protein. BCL2 homology 4 (BH4) domain is required for its antiapoptotic function, thus acts as a promising anticancer target [1].
BDA-366 is a selective BCL2 inhibitor. BDA-366 induced conformational change of BCL2 that exposed the BH3 domain, resulting in abrogation of its prosurvival function and conversion of BCL2 to a prodeath protein. In non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cells, BDA-366 selectively bound to BCL2 with high affinity. BDA-366 induced apoptosis by BCL2-dependent BAX activation and cytochrome c release. In H460 cells, BDA-366 reduced Bcl2/IP3R binding, which then increased Ca2+ release [1].
In mice bearing H460 lung cancer xenografts, treatment with BDA-366 (0, 10, 20, and 30 mg/kg/day) via i.p. route for 14 days induced apoptosis and potently inhibited tumor growth in a dose-dependent way. There was no significant toxicity at the maximum therapeutic dose. In tumor tissue from patients with NSCLC, BDA-366 synergized with RAD001 and resulted in significantly greater inhibition of lung cancer growth compared with either agent alone [1].
Reference:
[1]. Han B, Park D, Li R, et al. Small-Molecule Bcl2 BH4 Antagonist for Lung Cancer Therapy. Cancer Cell, 2015, 27(6): 852-863.