Abstract C201: A novel potent and selective inhibitor of PI3K/mTOR, GDC‐0980, currently in phase I clinical trials

Introduction: The phosphoinositide‐3 kinase (PI3K)/Akt signaling pathway is deregulated in a wide variety of cancers. Somatic activating mutations and amplifications in PI3K are common in multiple cancers including breast, colon, and lung cancer. PTEN, a phosphatase that converts PIP3 to PIP2 and thus has an opposing function to PI3K, is a commonly mutated tumor suppressor in multiple cancers including prostate and glioblastoma. Alterations of this pathway have been implicated in tumor initiation, progression, survival, angiogenesis, and metastasis. PI3K/Akt pathway activation has also been implicated in therapeutic resistance. Thus PI3K is considered to be a promising therapeutic target for cancer. Summary of Results: Medicinal chemistry efforts resulted in the discovery of GDC‐0980, a selective, orally bioavailable inhibitor of PI3 Kinase and mTOR kinase with promising pharmacokinetic and pharmaceutical properties. Here we report the first pre‐clinical profile of GDC‐0980. This compound is a potent ATP‐competitive Class I PI3 kinase inhibitor with an IC50 of 4.8 nM against the PI3K p110apha subunit, 26.8 nM p110beta, 6.7 nM p110delta, 13.8 nM p110gamma, and an mTOR Kiapp of 17.3 nM. GDC‐0980 demonstrates selectivity against a large panel of protein kinases as well as selectivity over PIK family kinases including Class II, Class III, and DNA‐PK. GDC‐0980 inhibits the PI3K signaling pathway in vitro causing a reversible G1 cell cycle arrest, and apoptosis induction in a subset of tumor cell lines. Levels of signaling pathway markers such as phosphorylated AKT (pAKT), PRAS40 (pPRAS40), and S6 (pS6) are rapidly and dramatically reduced following exposure of cells to GDC‐0980. Oral dosing of GDC‐0980 potently inhibits tumor growth in xenograft models including those mutated in PI3K and PTEN, and elicits an exposure‐related concomitant decrease in PD biomarkers. Conclusion: These preclinical data provide compelling evidence in support of GDC‐0980 as a clinical candidate, and Phase I studies are ongoing. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C201.