CNX-1351

CNX-1351 is a potent and isoform-selective targeted covalent PI3Kα inhibitor with IC₅₀ of 6.8 nM. IC50 & Target: IC50: 6.8 nM (PI3Kα), 166.0 nM (PI3Kβ), 240.3 nM (PI3Kγ), 3020.0 nM (PI3Kδ)^[1] In Vitro: CNX-1351 is able to potently (EC₅₀<100 nM) and specifically inhibit signaling in PI3Kα-dependent cancer cell lines, and this leads to a potent antiproliferative effect (GI₅₀<100 nM). CNX-1351 inhibits PI3K signaling in SKOV3 cells, with potency (EC₅₀ of 10-100 nM) similar to that of the pan-PI3K inhibitor. To investigate the functional consequence of inhibiting PI3Kα in cells, two cell lines with different PIK3CA activating mutations, SKOV3 ovarian cancer cells (H1047R) and MCF-7 breast cancer cells (E545K), are treated with CNX-1351 and growth is monitored. Both PIK3CA-driven cell lines are growth inhibited by exposure to CNX-1351 for 96 h (GI₅₀ of 78 and 55 nM, respectively)^[1]. In Vivo: CNX-1351 inhibits p-Akt^Ser473 in mouse spleens and bonds to PI3Kα in vivo. CNX-1351 is delivered into the intraperitoneal cavity of nude mice at 100 mg/kg once a day for 5 consecutive days (n=3 mice per group). Spleens are harvested from the mice at the indicated times after the last dose (1-24 h) and interrogated by immunoblot for P-Akt^Ser473 or for PI3Kα occupancy. Inhibition of PI3K signaling is detected as a decrease in P-Akt^Ser473 at 1 and 4 h after last dose^[1].