Padnarsertib

KPT-9274 is an orally bioavailable, dual PAK4/Nicotinamide phosphoribosyltransferase (Nampt) inhibitor, with IC₅₀s less than 100 and 120 nM, respectively. IC50 & Target:IC50: <100 nM (PAK4)^[1], 120 nM (NAMPT)^[2] In Vitro: KPT-9274 attenuates the PAK4/β-catenin pathway, results in NAD depletion, and attenuates viability, invasion, and migration in several RCC cell lines. Inhibition of NAMPT in a cell-free enzymatic assay using recombinant NAMPT shows an IC₅₀ of approximately 120 nM for KPT-9274. KPT-9274 attenuates G2–M transit and induces apoptosis in RCC cell lines^[2]. In Vivo: KPT-9274 demonstrates a decrement of xenograft growth comparable with that of sunitinib. There are minimal KPT-9274 effects on the normal human RPTECs and no apparent toxicity in vivo. KPT-9274 is currently being investigated in a phase I human clinical trial of patients with advanced solid malignancies and NHL^[2]. KPT-9274 (oral administation; 100mg/kg or 200 mg/kg; twice a day; 14 days) demonstrates a decrement of xenograft growth and exists no significant weight loss in animals receiving KPT-9274. 8 hours after, KPT-9274 are measured at the end of the experiment in mouse plasma and tumors with 10757 ng/ml and 10647 ng/ml, respectively^[3].