tcsc0089 Buparlisib

Buparlisib (NVP-BKM120) is a pan-class I PI3K inhibitor, with IC₅₀s of 52, 166, 116 and 262 nM for p110α, p110β, p110δ and p110γ, respectively.

IC50 & Target: IC50: 52 nM (p110α), 166 nM (p110β), 116 nM (p110δ), 262 nM (p110γ)^[1]

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^[1]. 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^[2].

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 pAKT^Ser473. Partial inhibition of pAKT^Ser473 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^[1]. 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)^[2].