ASTX660, a novel non-peptidomimetic antagonist of cIAP1/2 and XIAP, potently induces TNF-{alpha} dependent apoptosis in cancer cell lines and inhibits tumor growth

Due to their roles in the evasion of apoptosis, Inhibitor of Apoptosis Proteins (IAPs) are considered attractive targets for anti-cancer therapy. Antagonists of these proteins have the potential to switch pro-survival signaling pathways in cancer cells towards cell death. Various SMAC-peptidomimetics with inherent cIAP selectivity have been tested clinically and demonstrated minimal single agent efficacy. ASTX660 is a potent, non-peptidomimetic, antagonist of cIAP1/2 and XIAP, discovered using fragment-based drug design. The antagonism of XIAP and cIAP1 by ASTX660 was demonstrated on purified proteins, cells and in vivo in xenograft models. The compound binds to the isolated BIR3 domains of both XIAP and cIAP1 with nanomolar potencies. In cells and xenograft tissue direct antagonism of XIAP was demonstrated by measuring its displacement from caspase-9 or SMAC. Compound-induced proteasomal degradation of cIAP1 and 2, resulting in downstream effects of NIK stabilization and activation of non-canonical NF-B signaling, demonstrated cIAP1/2 antagonism. Treatment with ASTX660 led to TNF-α-dependent induction of apoptosis in various cancer cell lines in vitro, while dosing in mice bearing breast and melanoma tumor xenografts inhibited tumor growth. ASTX660 is currently being tested in a phase 1-2 clinical trial (NCT02503423) and we propose that its antagonism of cIAP1/2 and XIAP may offer improved efficacy over first-generation antagonists that are more cIAP1/2 selective.

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