PI3Kα-IN-29 is an efficacious, orally bioavailable, and selective PI3Kα inhibitor with an IC50 value of 2.5 nM. It demonstrates over 400-fold selectivity against PI3Kβ/δ/γ/mTOR. This compound selectively degrades the H1047R mutant p110α protein and inhibits PI3Kα kinase activity. PI3Kα-IN-29 suppresses the PI3K/AKT/mTOR signaling pathway, induces G1 phase arrest, and inhibits cell migration. Additionally, it impedes tumor growth in T47 mouse models and is applicable for breast cancer research.

PI3Kα:2.5 nM

PI3Kα-IN-29 (compound A32) exhibits potent antiproliferative effects on T47D and MCF7 cells with IC50 values of 0.157 and 0.373 μM, respectively. PI3Kα-IN-29 (0-5 μM, 0-24 hours) induces dose-dependent G1 phase arrest and inhibits cell migration by suppressing the PI3K/AKT/mTOR pathway. A32 (0.1-5 μM, 24 hours) also inhibits PI3K/AKT/mTOR signaling and induces the degradation of mutant p110α, the catalytic subunit of PI3Kα, in T47D cells. The compound forms a critical hydrogen bond with Val851 and a tripartite hydrogen bond network with Gln859 and Ser854, while the benzoxazole moiety interacts with Lys802, Ser774, and Ala775, resulting in potent PI3Kα inhibition. Additionally, PI3Kα-IN-29 (125 nM-2 μM, 14 days) inhibits MCF7 cell colony formation in a concentration-dependent manner.

PI3Kα-IN-29, administered orally at doses of 50 and 100 mg/kg once daily for 21 days, demonstrates significant in vivo antitumor efficacy and favorable safety in a T47D xenograft mouse model. Additionally, PI3Kα-IN-29 shows good safety in ICR mice when given as a single intragastric dose of 500, 1000, and 1500 mg/kg.