ETP-46321

ETP-46321 is a potent, selective, orally bioavailable dual PI3K α/δ inhibitor with IC50 of 2.3/14.2 nM, weakly inhibits p110β and p110γ with IC50 of 170 and 179 nM; shows highly selectivity versus mTOR and 288 representative kinases, also potently inhibits mutants PI3K α E542K, E545K, and H1047R with IC50 of ~2 nM, inhibits phosphorylation of AKT Ser473 in the U2OS cell line with IC50 of 8.3 nM; shows significant tumor growth inhibition and reduction of the tumor metabolic activity in a lung tumor mouse model driven by a K-RasG12V oncogenic mutation. (In Vitro) :ETP-46321 is selected to be screened against other PI3K isoforms. ETP-46321 is more potent against isoform α (Kiapp=2.3 nM) . ETP-4632, has been profiled and shown to be a potent PI3K α and δ inhibitor, highly selective versus mTOR and 288 representative kinases. ETP-46321 is also tested against three of the p110α mutant enzymes detected in human cancers (E542K, E545K and H1047R), being equipotent against these mutants when compared to the wild type protein (Kiapp=2.33, 1.77 and 1.89 nM for PI3Kα-H1047R, PI3Kα-E545K and PI3Kα-E542K, respectively) . ETP-46321 inhibits the phosphorilation of AKT in U2OS cell line with an IC50 of 8.3 nM. (In Vivo) :ETP-46321, is selected for in vivo studies based on its appealing pharmacokinetic profile in BALB-C mice, low in vivo Clearance (0.6 L/h/Kg) and good oral bioavailability (90%) . ETP-46321 demonstrates a good pharmacokinetic profile in mice and is selected for preliminary in vivo evaluation in a lung tumor mouse model driven by a K-RasG12V oncogenic mutation, showing significant tumor growth inhibition, and reduction of the tumor metabolic activity as measured by positron emission tomography (PET) techniques.