BTX306 (BTX-306) is a novel protein homeostatic modulator, potently reduces levels of GSPT1, eRF1, CK1α, MCL-1, and c-MYC in myeloma cells, overcomes bortezomib and lenalidomide resistance.BTX306 is much more potently reduced human-derived myeloma cell line viability, with median inhibitory concentrations in the single nanomolar range versus micromolar values for lenalidomide or pomalidomide, and more potently activated caspases 3/8/9.BTX306 did not impact viability of murine hematopoietic cells in an in vivo model, demonstrating its specificity for human cereblon.BTX306 did show some reduced activity in lenalidomide-resistant cell line models but nonetheless retained its nanomolar potency in vitro, overcame bortezomib resistance, and was equipotent against otherwise isogenic cell line models with either wild-type or knockout TP53.BTX306 demonstrated strong activity against primary CD138-positive plasma cells, showed enhanced anti-proliferative activity in combination with bortezomib and dexamethasone.BTX306 was effective in an in vivo systemic model of multiple myeloma.
