LY-3009120 Chemical Properties

Density 

1?+-.0.06 g/cm3(Predicted)

storage temp. 

Store at -20°C

solubility 

insoluble in H2O; insoluble in EtOH; ≥4.25 mg/mL in DMSO with gentle warming and ultrasonic

form 

solid

pka

13.52±0.70(Predicted)

color 

Light yellow to khaki

InChIKey

HHCBMISMPSAZBF-UHFFFAOYSA-N

SMILES

N(CCC(C)(C)C)C(NC1=CC(C2C(C)=NC3C(C=2)=CN=C(NC)N=3)=C(C)C=C1F)=O

Safety Information

HS Code 

2933998090

LY-3009120 Usage And Synthesis

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]

Synthesis

GENERAL PROCEDURE: 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (25.9 g, 68.5 mmol), 7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl trifluoromethanesulfonate (22.09 g 68.5 mmol) and sodium bicarbonate (17.28 g, 206 mmol) were dissolved in a solvent mixture of 1,4-dioxane (500 mL) and water (125 mL) and bubbled under argon protection for 20 min. Tetrakis(triphenylphosphine)palladium (3.96 g, 3.43 mmol) was added and the reaction was heated at 50 °C under argon atmosphere. Subsequently 7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl trifluoromethanesulfonate (300 mg, 0.55 mmol) was added by supplementation and heating was continued at 50 °C overnight. After completion of the reaction, the mixture was cooled to room temperature, the solid was collected by filtration and washed sequentially with water and ether. The resulting solid was treated with acetonitrile (50 mL) and stirred at 80 °C for 30 min, the solid was again collected by filtration, washed with acetonitrile and dried in vacuum at 80 °C to give a light yellow solid. The solid was further treated with methanol (50 mL), heated at 80 °C for 1 h. After cooling to room temperature, the solid was filtered, washed with methanol (20 mL) and dried under vacuum to afford the target product 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (22.5 g, yield 77%), as a light yellow solid. Mass spectrum (m/z): 425.2 (M + 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.

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