Toxicity Profile of Small-Molecule IAP Antagonist GDC-0152 Is Linked to TNF-α Pharmacology

Inhibitor-of-apoptosis (IAP) proteins suppress apoptosis and are overexpressed in a variety of cancers. Small-molecule IAP antagonists are currently being tested in clinical trials as novel cancer therapeutics. GDC-0152 is a small-molecule drug that triggers tumor cell apoptosis by selectively antagonizing IAPs. GDC0152 induces NF-κB transcriptional activity leading to expression of several chemokines and cytokines, of which tumor necrosis factor alpha (TNF-α) is the most important for single-agent tumor activity. TNF-α is a pleiotropic cytokine that drives a variety of cellular responses, comprising in�耀ammation, proliferation, and cell survival or death depending on the cellular context. As malignant and normal cells produce TNF-α upon IAP antagonism, increased TNF-α could drive both ef�耀cacy and toxicity. The toxicity pro�耀le of GDC-0152 in dogs and rats was characterized after iv dose administration once every 2 weeks for four doses. Findings in both species consisted of a dose-related, acute, systemic in�耀ammatory response, and hepatic injury. Laboratory �耀ndings included elevated plasma cytokines, an in�耀ammatory leukogram, and increased liver transaminases with histopathological �耀ndings of in�耀ammatory in�耀ltrates and apoptosis/necrosis in multiple tissues; a toxicology pro�耀le consistent with TNF-α-mediated toxicity. Dogs exhibited more severe �耀ndings than rats, and humans did not exhibit these �耀ndings, at comparable exposures across species. Furthermore, elevations in blood neutrophil count, serum monocyte chemoattractant protein-1, and other markers of in�耀ammation corresponded to GDC-0152 exposure and toxicity and thus