BTSA1 Activates BAX to Promote Apoptosis in Acute Myeloid Leukemia

BAX is a proapoptotic BCL2 family protein that can be suppressed by overexpression of antiapoptotic BCL2 proteins to promote tumorigenesis and resistance to therapy in cancer. Clinical inhibitors of antiapoptotic BCL2 proteins are available, including venetoclax, and can promote BAX/BAK-mediated apoptosis, but they have limited efficacy in tumors that overexpress additional antiapoptotic proteins. Most cancer cells express BAX in an inactive conformation or suppressed by antiapoptotic proteins, suggesting the possibility for therapeutic activation of BAX to promote apoptosis in cancer. In order to develop a BAX activating compound, Reyna and colleagues performed structure-based drug design and chemical synthesis combined with a competitive fluorescence polarization assay to screen compounds for binding to the N-terminal BAX activation site (trigger site). The lead compound, BAX Trigger Site Activator 1 (BTSA1), exhibited potent and selective BAX activation, inducing a conformational change to transform inactive cytosolic BAX to its active oligomeric form capable of triggering apoptosis. BTSA1 treatment induced apoptosis in human acute myeloid leukemia (AML) cell lines, but not in BAX-deficient cells. Further, BTSA1 induced apoptosis of primary AML blast cells and preleukemic stem cells, which expressed high levels of BAX, in a dose-dependent manner, but did not affect healthy hematopoietic stem and progenitor cells. BTSA1 also synergized with venetoclax to promote AML cell apoptosis in vitro. In vivo, BTSA1 was well tolerated, having no effect on normal hematopoiesis, orally bioavailable, and had excellent pharmacokinetics. BTSA1 treatment induced apoptosis to suppress the growth of human AML xenografts. The identification of BTSA1 as a potent and selective BAX activator suggests the feasibility of therapeutically activating BAX to promote cancer cell apoptosis, and BTSA1 exhibited antileukemic activity both in vitro and in vivo.

Reyna DE, Garner TP, Lopez A, Kopp F, Choudhary GS, Sridharan A, et al. Direct activation of BAX by BTSA1 overcomes apoptosis resistance in acute myeloid leukemia. Cancer Cell 2017;32:490–505.e10.

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