P7170, A Novel Inhibitor Of Phosphoinositide 3-Kinase (Pi3k)-Mammalian Target Of Rapamycin (Mtor) And Activin Receptor-Like Kinase 1 (Alk1) As A New Therapeutic Option For Kras Mutated Non Small Cell Lung Cancer (Nsclc)

Major breakthroughs in targeted cancer treatment have been achieved in last decade, but still some patient populations such as Kras mutated non small cell lung cancer (NSCLC), have no therapeutic options other than cytotoxic therapies. Therefore, development of targeted therapeutics is warranted in order to provide improved survival benefit for NSCLC patients with Kras mutation. P7170 is a small molecule inhibitor of PI3K (IC50 = 2.2 nM) and mTOR (IC50 = 4.4 nM). It also inhibits ALK1 and DNA-PK, two important enzymes involved in angiogenesis and DNA repair with IC50 of 47 and 1.5 nM, respectively. The structure, other in vitro, and in vivo efficacy of P7170 has been reported in the accompanying abstract submitted for AACR 2012. P7170 inhibited PI3K-mTOR pathway proteins pAKT, pS6 and p4EBP1 by 90 to 100 % in Kras mutated NSCLC cell line (H460) in a western blot assay. P7170 also exhibited potent cytotoxicity activity against two Kras mutated NSCLC (H460 and A549) cell lines with IC50 values of 7 and 5 nM. P7170 inhibited anchorage independent colony formation of tumor cells isolated from 10 different human tumor xenografts derived from NSCLC patient9s tumors (Seven out of 10 samples had wild type Kras, and three had mutations in Kras). Moreover, P7170 induced apoptosis in H460 cell lines by inducing PARP cleavage. More interestingly, P7170 inhibited pAKT and pS6 in a dose dependent fashion in stem-like cells isolated from tumor samples of a Kras mutated NSCLC patient. P7170 demonstrated significant (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3759. doi:1538-7445.AM2012-3759