Abstract 627: Etp-47187 a novel potent and efficacious dual inhibitor of phosphoinositide-3-kinases and mTOR

Abstract

Abstract The phosphoinositide-3-kinase (PI3K) signaling pathway is activated in a variety of solid and non-solid tumors. In many instances this is due to either activating mutations in the catalytic subunit of PI3Kα, p110α, or inactivating mutations or deletions of the tumor suppressor PTEN. In addition, the PI3K pathway is activated by mutations in certain receptor tyrosine kinases as well as by mutation of the oncogene KRAS. All of these lesions lead to enhanced activity of both PI3K and mTOR. Hence there is great interest to discover inhibitors of PI3K and mTOR for the treatment for cancer. Following a rational design strategy, we identified the fused thiadiazole derivative ETP-47187 as a potent dual inhibitor of PI3Kα and mTOR Kis = 0.18 nM and 1.2 nM, respectively. ETP-47187 also inhibits three oncogenc mutants of p110α: p110α E542K Ki = 0.38 nM, p110α E545K Ki = 0.2 nM and p110α H1047R Ki = 0.29 nM as well as PI3Kβ, PI3KΔ and PI3Kγ Kis 2.7, 0.26 and 1.5 nM, respectively. The compound inhibits PI3K signaling in treated tumor cell lines; the EC50 for inhibition of the phosphorylation of Akt was 5 nM. ETP-47187 has a pharmacokinetic profile suitable for oral dosing in mice (%F = 73%, Cl = 0.11 L/hr/kg; Vds = 0.38 L/h/kg). Treatment of tumor bearing mice with the compound causes a dose dependent reduction in P-Akt levels in the tumor. Once a day treatment of mice bearing human tumor xenografts with ETP-47187 results in significant tumor growth delay and is well tolerated. In a mouse model of lung cancer induced by expression of an oncogenic mutant KRAS, treatment with ETP-47187 blocked tumor growth and lead to a significant PET response. These and combination data will be discussed. We believe ETP-47187 and compounds like it are suitable to propose for clinical development in cancer patients with activated PI3K signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 627. doi:10.1158/1538-7445.AM2011-627