Definition

An orally bioavailable mimetic of the natural second mitochondrial-derived activator of caspases (Smac), with potential apoptotic-inducing, chemo-radio-sensitizing and antineoplastic activities. Upon oral administration, Smac mimetic BGB-24714 targets and binds to the Smac binding groove on inhibitor of apoptosis proteins (IAPs), including the direct caspase inhibitor X chromosome-linked IAP (XIAP), and the cellular IAPs 1 (c-IAP1) and 2 (c-IAP2). This inhibits the activities of these IAPs and promotes the induction of apoptosis through apoptotic signaling pathways. IAPs are overexpressed by many cancer cell types and suppress both intrinsic and extrinsic apoptosis by binding to and inhibiting active caspases via their baculoviral lAP repeat (BIR) domains. They contribute to chemo-radio-resistance of cancer cells to certain cytotoxic agents and radiation, promote tumor cell survival and are associated with poor prognosis in certain types of cancer. Smac, a pro-apoptotic mitochondrial protein, is an endogenous inhibitor of the IAPs family of cellular proteins.