Description
Buparlisib (944396-07-0) is potent pan-Class I PI3-kinase inhibitor (IC50’s: p110α = 52 nM, p110 = 166 nM, p110δ = 116 nM. P110g = 262 nM).1,2 It inhibited microtubule dynamics at in vitro concentrations >1μM and doses above 50mg/kg in mice.3 Buparlisib lead to a precipitous drop in DNA synthesis in a mouse model of BRCA1-linked triple-negative breast cancer with less affect in normal tissue.4
Uses
NVP-BKM 120 is a novel anti-tumor active compound that is selective in that it inhibits specifically PI3 kinase activating cell death in glioma cells. Glioma cells being those that proliferate from tumors in the brain or the spine.
Uses
A selective Class I PI3K inhibitor of p110α, p110β, p110δ and p110γ with IC50s of 50-300 nM.
Definition
ChEBI: BKM120 is an aminopyridine that is 4-(trifluoromethyl)pyridin-2-amine substituted at position 5 by a 2,6-di(morpholin-4-yl)pyrimidin-4-y group. A selective PI3K inhibitor with anti-tumour properties. It has a role as an EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor and an antineoplastic agent. It is a member of morpholines, an aminopyrimidine, an aminopyridine and an organofluorine compound.
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[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].
IC 50
p110α: 52 nM (IC
50); p110α-H1047R: 58 nM (IC
50); p110α-E545K: 99 nM (IC
50); p110δ: 116 nM (IC
50); p110β: 166 nM (IC
50); p110γ: 262 nM (IC
50); Vps34: 2.4 μM (IC
50); mTOR: 4.6 μM (IC
50)
References
[1] MATTHEW T. BURGER*. Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer[J]. ACS Medicinal Chemistry Letters, 2011, 2 10: 774-779. DOI:
10.1021/ml200156t[2] SAUVEUR-MICHEL MAIRA. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor.[J]. Molecular Cancer Therapeutics, 2012, 11 2: 317-328. DOI:
10.1158/1535-7163.mct-11-0474[3] SASKIA M BRACHMANN. Characterization of the mechanism of action of the pan class I PI3K inhibitor NVP-BKM120 across a broad range of concentrations.[J]. Molecular Cancer Therapeutics, 2012, 11 8: 1747-1757. DOI:
10.1158/1535-7163.mct-11-1021[4] ASHISH JUVEKAR. Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion.[J]. Proceedings of the National Academy of Sciences of the United States of America, 2016, 113 30: E4338-47. DOI:
10.1073/pnas.1522223113
