The Inhibitor of Apoptosis Proteins (IAPs) are key regulators of anti-apoptotic and pro-survival signalling pathways. Overexpression of IAPs occurs in a number of cancer types and has been associated with tumour progression and resistance to treatment. IAPs have been proposed as targets for anticancer therapy, and a number of peptidomimetic IAP antagonists have entered clinical trials.<br/>We have successfully applied our fragment-based screening approach, Pyramid<sup>TM</sup>, to identify non-peptidic fragments binding with millimolar affinities to both cellular inhibitor of apoptosis 1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP). Structure based hit optimisation guided by X-ray crystallography, computational studies and NMR solution conformational analysis allowed us to significantly increase the binding affinity of the starting hits.<br/>The subsequent lead optimization campaign focused on reducing off-target activity and improving pharmacokinetic properties. This resulted in ASTX660, a potent non-peptidic IAP antagonist which is structurally distinct from all previously reported IAP antagonists. ASTX660 is currently being tested in a phase 2 clinical trial (NCT02503423) and we propose that its unique dual antagonism of cIAP1 and XIAP may offer improved efficacy over more cIAP selective antagonists.

ASTX660, the first fragment-derived IAP antagonist in the clinic

255th National Meeting (2018)

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