The small molecule BDA-366 selectively inhibits BCL2, converting it to a cell death inducer.

  • Major finding: The small molecule BDA-366 selectively inhibits BCL2, converting it to a cell death inducer.

  • Mechanism: BDA-366 binds the BCL2 BH4 domain, exposing the BH3 domain and activating BAX to drive apoptosis.

  • Impact: BDA-366, alone or in combination with mTOR inhibition, may be effective against human lung cancer.

Upregulation of antiapoptotic BCL2 family members is implicated in treatment-resistant lung cancers. The BCL2 homology 4 (BH4) domain is required for the antiapoptotic function of BCL2, leading Han and colleagues to seek a selective BCL2 BH4 antagonist for the treatment of lung cancer. The small-molecule BCL2 BH4 domain antagonist BDA-366 was identified as the most effective compound against human lung cancer cell lines, including both small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC) cells. Sensitivity to BDA-366 was dependent on both BCL2 expression and BH4 binding, and BDA-366 selectively bound with high affinity to BCL2, but not to other BCL2 family members. In vitro cell-free assays demonstrated that BDA-366 induced a conformational change in BCL2 that exposed the BH3 domain, resulting in abrogation of its prosurvival function and conversion to a prodeath protein. BDA-366–induced apoptosis was mediated by BCL2-dependent BAX activation and cytochrome c release. In vivo experiments using xenografts derived from NSCLC cell lines or from a patient with refractory SCLC revealed that BDA-366 induced apoptosis and potently suppressed tumor growth in a dose-dependent manner without significant toxicity to mice at the maximum therapeutic dose. Consistent with in vitro findings, apoptosis in xenograft tumors was mediated by BDA-366–induced exposure of the BCL2 BH3 domain and increased activation of BAX. Furthermore, in lung cancer cell lines and tumor tissue from patients with NSCLC, inhibition of mTOR by RAD001 (everolimus) resulted in upregulation of BCL2. Addition of BDA-366 synergized with RAD001 and resulted in significantly greater inhibition of lung cancer growth compared with either agent alone. In summary, this study identifies the small-molecule BDA-366 as a selective inhibitor of BCL2, elucidates the mechanism that converts BCL2 to a prodeath protein, and provides a rationale for cotargeting BCL2 and mTOR in lung cancer therapy.

Han B, Park D, Li R, Xie M, Owonikoko TK, Zhang G, et al. Small-molecule BCL2 BH4 antagonist for lung cancer therapy. Cancer Cell 2015 May 21 [Epub ahead of print].