PI3Kα-IN-4 is a potent, selective, and orally active PI3Kα inhibitor with an IC50 of 1.8 nM, demonstrating antitumor activity [1].

PI3Kα:1.8 nM (IC50)

PI3Kα-IN-4 (compound 10) inhibits PI3Kα, β, δ, and γ in kinase assays with IC50s of 1.8, 271.0, 13.9, and 13.8 nM, respectively, and in cell-based assays with IC50s of 12.1, 1393, 183, and >10000 nM, respectively [1].

PI3Kα-IN-4 (compound 10) (30 mg/kg; p.o. once daily for 21 days) achieves 73.0% tumor growth inhibition in mice. It dose-dependently suppresses tumor growth by 62.5% (15 mg/kg), 86.0% (30 mg/kg), and 90.7% (40 mg/kg) when administered orally once daily for 30 days. Time- and dose-dependent inhibition of Akt phosphorylation is observed in vivo (15-40 mg/kg; p.o. once daily; 1-4 h). The compound shows high Cmax (mouse 22167, rat 2327 nM) and good bioavailability (mouse 59.4%, rat 46.9%) after oral administration (mouse 10, rat 3 mg/kg). Following intravenous injection (mouse 1, rat 1 mg/kg), it has a t1/2 of 0.99 hours in mice and 1.22 hours in rats, with low plasma clearance (mouse 4.16, rat 5.28 mL/min/kg).