Inhibitor of apoptosis (IAP) antagonists are being tested in the clinic for the treatment of cancer as they can switch cancer cell TNFα signalling from being pro-survival to being pro-apoptotic, and
relieve the block on effector caspase activation (1,2). Astex has used fragment based-drug discovery to develop a first-in-class, dual XIAP/cIAP1 antagonist (ASTX660), which is non-peptidomimetic,
does not contain an alanine as a warhead and demonstrates prolonged antagonism of both XIAP and cIAP1 in vivo.
Melanoma is a highly aggressive malignancy with an exceptional ability to develop resistance to targeted therapies. Targeting IAP proteins in melanoma is a promising strategy to overcome this
resistance (3), and ASTX660 represents a novel approach because of the enhanced potency against XIAP (4).
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2014 EORTC: Induction of apoptosis with a novel dual cIAP1/XIAP antagonist in models of melanoma