BTSA1.2 is a potent, selective, orally bioavailable BAX activator, demonstrated increased binding to BAX (IC50=149 nM) compared to BTSA1 (IC50=247 nM).
BTSA1.2 also showed more potent cellular activity in a set of lymphoma cell lines compared to BTSA1(SU-DHL-4 IC50 1.24 uM vs2.29 uM, SU-DHL-6 IC50 1.75 uM vs2.6 uM).
BTSA1.2 directly engaging with cellular BAX.
BTSA1.2 demonstrated favorable properties by oral administration such as substantial half-life (T1/2 ~14 h) in mouse plasma, favorable oral bioavailability (%F ~50%) and significant plasma exposure (AUC-100 uΜ h).
BTSA1.2 treatment showed significantly better cytotoxicity in leukemia and lymphoma cell lines (mean IC50<3 uM) than in most solid tumor cell lines (mean IC50>10 uM).
BTSA1.2 and Navitoclax synergize to inhibit cell viability and induce apoptosis in various tumor cell lines.
Combination of BTSA1.2 and Navitoclax is well tolerated and does not enhance Navitoclax driven toxicity in the hematopoietic system, shows potent efficacy in resistant colorectal tumor xenografts.
BTSA1.2, a rationalized BTSA1 analog, has improved binding to BAX, cellular cytotoxicity, and is better-tolerated in vivo.