BDA-366

**BDA-366** is a small-molecule antagonist of the BCL2 BH4 domain, belonging to the anthraquinone class (1,4-diamino-9,10-anthraquinone). It binds with high affinity (Ki = 3.3 nM) to induce a conformational change in BCL2, exposing its BH3 domain, converting the anti-apoptotic protein into a pro-apoptotic "death protein," and promoting apoptosis in cancer cells. Developed through the National Cancer Institute's Developmental Therapeutics Program, it demonstrates potent activity against multiple myeloma (MM), non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), chronic lymphocytic leukemia (CLL), and diffuse large B-cell lymphoma (DLBCL) cell lines and primary samples, suppressing xenograft tumor growth in mice without significant toxicity to normal hematopoietic cells or body weight. Additional effects include BCL2 dephosphorylation at Ser70, PI3K/AKT pathway inhibition, and Mcl-1 downregulation, distinguishing it from BH3 mimetics like venetoclax, with which it shows synergy.[1][2][3][4][7][10]