LY-3009120

Uses

LY 3009120 is a potent pan-Rad inhibitor used in the inhibition of tumors. Dose-dependant inhibition.

Definition

ChEBI: LY3009120 is a member of the class of pyridopyrimidines that is pyrido[2,3-d]pyrimidine substituted by methylamino, 5-{[(3,3-dimethylbutyl)carbamoyl]amino}-4-fluoro-2-methylphenyl, and methyl groups at positions 2, 6 and 7, respectively. It is a potent pan RAF inhibitor which inhibits BRAF(V600E), BRAF(WT) and CRAF(WT) (IC50 = 5.8, 9.1 and 15 nM, respectively). It also inhibits RAF homo- and heterodimers and exhibits anti-cancer properties. It has a role as a necroptosis inhibitor, an apoptosis inducer, an antineoplastic agent, a B-Raf inhibitor and an autophagy inducer. It is a pyridopyrimidine, a biaryl, an aromatic amine, a member of phenylureas, a member of monofluorobenzenes, an aminotoluene and a secondary amino compound.

Biological Activity

ly3009120 is a pan-raf and raf dimer inhibitor. it inhibits braf wt, craf, wt, brafv600e, and brafv600e+g468a with the ic50 values of 9.1, 15, 5.8, and 17 nm, respectively. [1]raf is family of serine/threonine-protein kinase mediates ras gtpases and the mapk/erk cascade. it involves in proliferation, differentiation, apoptosis, survival and oncogenic transformation. [1]in nras mutant sk-mel2 cells or kras mutant hct116 cells, ly3009120 inhibits the kinase activity of craf in a dose-dependent manner and induces braf/craf heterodimerization. it also blocks phospho-mek and -erk and induces minimal paradoxical activation in ras mutant cells. moreover, treatment of braf v600e a375 melanoma cells by ly3009120 for 24 hr predominantly induces a g0/g1 arrest with more than 95% cells in g0/g1 phase. [1]in nude rats bearing a375 xenograft tumors, oral ly3001920 treatment exerts a dose-dependent inhibition of phospho-mek and –erk. 15 or 30 mg/kg ly3009120 shows near complete tumor regression in nude rats bearing pdx tumors. [1]

in vivo

IC 50

BRaf^V600E: 5.8 nM (IC₅₀); Braf: 9.1 nM (IC₅₀); CRAF: 15 nM (IC₅₀)

storage

Store at -20°C

References

1. peng sb, henry jr, kaufman md et al. inhibition of raf isoforms and active dimers by ly3009120 leads to anti-tumor activities in ras or braf mutant cancers. cancer cell. 2015 sep 14;28(3):384-98.