Small Molecule Bda-366 As a Bcl2-BH4 Antagonist for Multiple Myeloma Therapy

Multiple myeloma (MM) is the most common hematological malignancy in USA, characterized with excessive abnormal clonal plasma cells in the bone marrow. Despite the great improvement in MM treatment by targeting the normal plasma cell biology of the cells during the last decade, the disease still remains incurable. B-cell lymphoma-2 (Bcl2) protein has four domains: BH1 (Bcl2 homology domain 1), BH2, BH3 and BH4, and plays critical roles in promoting the survival and drug-resistant of MM cells. Unlike the BH1, BH2, and BH3 domains, the BH4 region is responsible for the anti-apoptotic function of Bcl2 protein. Current BH3-mimetic and other Bcl2 inhibitors have been trailed in clinic but showed limited therapeutic efficacy. We recently identified a small molecule BDA-366 as a Bcl2-BH4 domain antagonist with potent anti-MM effect. BDA-366 bound to the BH4 resulted in the decrease of Bcl2 phosphorylation and the exposure of the BH3 domain as detected by anti-Bcl2-BH3 antibodies. Consequently, BDA-366 treatment induced robust apoptotic death on both human MM cell lines (RPMI8226 and U266) and primary MM cells from patients. In NOD-scid/IL2Rγ^null (NSG) murine xenograft model, administration of BDA-366 (20mg/kg/day, 5 doses) markedly suppressed the growth of human MM tumor cells in vivo. We propose that BDA-366 as a novel BH4-based anti-MM agent could provide a more efficient pharmacological approach to treat MM.