BKM-120

Description

Buparlisib (BKM120, NVP-BKM120) is a selective PI3K inhibitor of p110α/β/δ/γ with IC50 of 52 nM/166 nM/116 nM/262 nM in cell-free assays, respectively. Reduced potency against VPS34, mTOR, DNAPK, with little activity to PI4Kβ. Phase 2.
BKM120 has many different types and subtypes of PI3K. Type 1 PI3K has a catalytic subunit which called p110. There are four types (isotypes)-p110α, p110β, p110γ, and p110δ.

In vitro

BKM120 is not sensitive to Class III and Class IV PI3K's or PI4K. NVP-BKM120 shows great antiproliferation activity to PI3K deregulated cell lines including A2780, U87MG, MCF7 and DU145 with GI50 of 0.1-0.7 nM. BKM120 induces multiple myeloma cells (ARP1, ARK, MM.1S, MM1.R and U266) apoptosis, which results in increased G1-phase cells and decreased S-phase cells. BKM120 induced CD138+ primary MM cell apoptosis and has significant lower cytotoxicity toward CD138? stromal cells. BKM120 exposure could cause upregulation of BimS and downregulation of XIAP. BKM120 demonstrates antiproliferative activity in human gastric cancer cell lines by decreasing mTOR downstream signaling. BKM120 could increase either p-ERK or p-STAT3 in KRAS mutant gastric cancer cells. Combination with STAT3 blockade, BKM120 shows a synergism in cells harboring mutated KRAS by inducing apoptosis, but not in KRAS wild-type cells. A recent study shows that BKM120 shows differential forms of cell death on the basis of p53 status of the cells with p53 wild-type cells undergoing apoptotic cell death and p53 mutant/deleted cells having a mitotic catastrophe cell death. BKM120 mediates mitotic catastrophe mainly through Aurora B kinase.

In vivo

BKM120 completely inhibits pAktser473 in A2780 xenograft tumors at doses of 30, 60, or 100 mg/kg, respectively. BKM120 also shows antitumor activity against U87MG glioma model at doses of 30 and 60 mg/kg. BKM120 treatment results in significantly reduced tumor volume and level of circulating human kappa chain at 5 μM/kg/day?1in ARP1 SCID mouse model, with prolonged survival.

Uses

BKM120 (PI3K inhibitor) is a small molecule orally available pan-I phosphoinositide 3-kinase inhibitor. Inositol mesylate 3-kinase inhibitors (PI3K inhibitors) are a class of medical drugs that inhibit one or more of the enzymes of functional phosphoinositide 3-kinase, which are part of the PI3K/AKT/mTOR pathway.

Uses

A selective Class I PI3K inhibitor of p110α, p110β, p110δ and p110γ with IC50s of 50-300 nM.

Definition

ChEBI: 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.