The inhibitor of apoptosis proteins (IAPs) are key regulators of apoptosis and pro-survival pathways. Overexpression of IAPs has been associated with tumour progression and resistance to treatment. As a result, IAPs have been proposed as anticancer therapeutic targets and several IAP antagonists have entered clinical trials. Binding of antagonists to cellular inhibitor of apoptosis proteins (cIAPs) causes auto-ubiquitinaton and degradation of the protein. We have successfully applied our fragment-based screening approach, PyramidTM discovery platform, to identify non-peptidic fragments binding with millimolar affinities to both cellular inhibitor of apoptosis protein 1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP). Structure-based hit optimisation guided by computational studies and NMR solution conformational analysis allowed us to significantly increase the binding affinity of the starting hits. The subsequent lead optimisation campaign resulted in ASTX660, a potent non-peptidic antagonist of cIAPs and XIAP, structurally distinct from all previously reported antagonists. Potent cIAP degradation has been demonstrated with ASTX660 in multiple in vitro and in vivo models and the compound is currently being tested in a Phase I/II clinical trial (NCT02503423) in cancer patients, where we have seen deep and sustained cIAP1 suppression in peripheral blood mononuclear cells (PBMCs) sampled from ASTX660-treated patients.

ASTX660, a small molecule antagonist and degrader of cellular inhibitor of apoptosis proteins in phase I/II clinical trials

2019 Fall National Meeting

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