Inhibitor of apoptosis proteins (IAPs), which block various signaling pathways leading to apoptotic cell death, are commonly over-expressed in cancer cells. GDC-0152 is a potent inhibitor of specific IAPs that binds baculoviral IAP repeat (BIR) domains (Kis = 28, 14, 17, and 43 nM for XIAP BIR3, NL-IAP BIR, BIRC2 (c-IAP1) BIR3, and BIRC3 (c-IAP2) BIR3, respectively). GDC-0152 induces activation of caspases, decreasing the viability of cancer cells without affecting normal cells. It is orally bioavailable and suppresses tumor growth in breast cancer xenografts in mice. GDC-0152 also induces NF-κB transcriptional activity, resulting in the expression of several cytokines, including TNF-α. In dogs and rats, but not humans, this leads to a pronounced inflammatory response.
