NVP-BKM120

NVP-BKM120 (BKM-120, Buparlisib) is a potent, selective, orally bioavailable inhibitor of class I PI3K isoforms with IC50 of 52 nM/166 nM/116 nM/262 nM for p110α/β/δ/γ, respectively; much less effectively inhibits the class III PI3K Vps34 and mTOR, and has no effect on PI4Kβ and several other kinases; prevents the growth of assorted cancer cell lines when used at 5 μM and inhibits tumor growth in vivo.Blood Cancer Phase 2 Clinical (In Vitro) :Buparlisib (NVP-BKM120) exhibits 50-300 nM activity for class I PI3K’s, including the most common p110α mutants. Additionally, NVP-BKM120 exhibits lower potency against class III and class IV PI3K's, where 2, 5, >5, and >25 μM biochemical activity is observed for inhibition of VPS34, mTOR, DNAPK, and PI4K, respectively. Buparlisib (NVP-BKM120) induces multiple myeloma (MM) cell apoptosis in both dose- and time-dependent manners. Buparlisib (NVP-BKM120) at concentrations ≥10 μM induces significant apoptosis in all tested MM cell lines at 24 h (P<0.05, compares with control) . Therefore, 10 μM Buparlisib (NVP-BKM120) and 24-h treatment are chose in in the following experiments if not stated otherwise. Buparlisib (NVP-BKM120) treatment results in a dose-dependent growth inhibition in all tested MM cell lines. Buparlisib (NVP-BKM120) IC50 varies among tested MM cells. At 24 h treatment, IC50 for ARP-1, ARK, and MM.1R is between 1 and 10 μM, while IC50 for MM.1S is <1 μM, and IC50 for U266 is between 10 and 100 μM. In summary, NVP-BKM120 treatment results in MM cell growth inhibition and apoptosis in dose- and time-dependent manners. (In Vivo) :In A2780 xenograft tumors, oral dosing of Buparlisib (NVP-BKM120) at 3, 10, 30, 60, and 100 mg/kg results in a dose dependent modulation of pAKTSer473. Partial inhibition of pAKTSer473 is observed at 3 and 10 mg/kg, and near complete inhibition is observed at doses of 30, 60, or 100 mg/kg, respectively. Inhibition of pAKT (normalized to total AKT) tracked well with both plasma and tumor drug exposure. Mice receiving Buparlisib (NVP-BKM120) (5 μM per kg per day for 15 days) treatment has significantly smaller tumor burdens as compare with control mice, which are measured as tumor volume (P<0.05) and level of circulating human kappa chain (P<0.05) . In addition, NVP-BKM120 treatment significantly prolongs the survival of tumor-bearing mice (P<0.05) .