PF-4989216

PF-4989216 is a potent and selective PI3Kα inhibitor with a K_i of 0.6 nM. IC50 & Target: Ki: 0.6 nM (PI3Kα), 1440 nM (mTOR)^[1] In Vitro: PF-4989216 (Compound 10) has excellent PI3Kα K_i (0.6 nM), good cellular potency (S473 IC₅₀=79 nM), and good selectivity against mTOR (mTOR K_i=1440 nM). PF-4989216 has PI3Kα K_i less than 1 nM and mTOR K_i more than 1 μM. PF-4989216 also has excellent selectivity over 40 other kinases, and no major CYP inhibitions are observed. Less than 30% inhibition is observed in 1A2, 2C9, 2D6, and 3A4 CYP enzymes at 3 μM^[1]. The toxicity of PF-4989216 in several drug-sensitive and MDR cancer cell lines, including cells overexpressing ABCB1 or ABCG2, and in HEK293 cells transfected with human ABCB1 or ABCG2 is determined. PF-4989216 inhibits human colon carcinoma S1 cell line and ABCG2-overexpressing subline S1-M1-80 with IC₅₀s of 1.11±0.09 and 6.79±1.00 uM, respectively. PF-4989216 inhibits human breast carcinoma MCF-7 and ABCG2-overexpressing sublines MCF7-FLV1000 and MCF7-AdVp3000 IC₅₀s of 2.30±0.68, 23.26±2.94 and 62.57±5.46 uM, respectively. PF-4989216 inhibits pcDNA-HEK293, ABCB1-transected MDR19-HEK293, ABCG2-tranfected R482-HEK293 cells with IC₅₀s of 0.44±0.05, 0.38±0.06 and 5.05±0.89 uM, respectively^[2]. In Vivo: PF-4989216 (Compound 10) is dosed orally in our in vivo antitumor model, PI3K driven NCI-H1975 xenograft tumors. PF-4989216 demonstrates dose responsive tumor growth inhibitory activity from 25 to 200 mg/kg in QD oral dosing^[1].