GDC-0980IsaNovelClassIPI3K/mTORKinaseInhibitorwith RobustActivityinCancerModelsDrivenbythePI3KPathway

Alterations of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway occur broadly in cancer via multiple mechanisms including mutation of the PIK3CA gene, loss or mutation of phosphatase and tensin homolog(PTEN), and deregulation of mammaliantargetof rapamycin (mTOR) complexes. The dysregulation of this pathway has been implicated in tumor initiation, cell growth and survival, invasion and angiogenesis, thus, PI3K and mTOR are promising therapeutic targets for cancer. We discovered GDC-0980, a selective, potent, orally bioavailable inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2) with excellent pharmacokinetic and pharmaceuticalproperties. GDC-0980potently inhibitssignaltransductiondownstream of both PI3K and mTOR, as measured by pharmacodynamic (PD) biomarkers, thereby acting upon two key pathway nodes to produce the strongest attainable inhibition of signaling in the pathway. Correspondingly, GDC-0980waspotentacrossabroadpanelofcancercelllines,withthegreatestpotencyinbreast,prostate,and lung cancers and less activity in melanoma and pancreatic cancers, consistent with KRAS and BRAF acting as resistancemarkers.TreatmentofcancercelllineswithGDC-0980resultedinG1cell-cyclearrest,andincontrast