ETP-46321 is an effective and orally bioavailable PI3Kα/PI3Kδ inhibitor (Ki: 2.3/14.2 nM).

p110α:2.3 nM (Ki), p110γ:179 nM (Ki), p110δ:14.2 nM (Ki), PI3Kα (E542K):1.89 nM (Ki), p110β:170 nM (Ki), PI3Kα (E542K):1.77 nM (Ki), PI3Kα (H1047R):2.33 nM (Ki)

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 phosphorylation of AKT in the U2OS cell line (IC50: 8.3 nM).

ETP-46321 has been chosen for in vivo studies due to its promising pharmacokinetic profile in BALB-C mice, characterized by low in vivo Clearance (0.6 L/h/Kg) and high oral bioavailability (90%). This selection was further justified for a preliminary in vivo evaluation in a lung tumor mouse model influenced by a K-RasG12V oncogenic mutation, where it exhibited notable tumor growth inhibition.

BALB/C mice are treated daily with ETP-46321 (50 mg/kg, p.o.) for three weeks. Tumor volumes of four mice in each treatment group are measured and compared to the starting volume at the beginning of the treatment.

DMSO: 30 mg/mL (63.35 mM), Sonication is recommended.