1454682-72-4
1454682-72-4 structure
- Name: LY 3009120
- Chemical Name: N-(3,3-Dimethylbutyl)-N'-[2-fluoro-4-methyl-5-[7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl]phenyl]urea
- CAS Number: 1454682-72-4
- Molecular Formula: C23H29FN6O
- Molecular Weight: 424.514
- Catalog: Signaling Pathways Autophagy Autophagy
- Create Date: 2018-12-26 18:45:04
- Modify Date: 2024-01-02 11:17:20
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LY3009120 is a pan RAF inhibitor which inhibits BRAFV600E, BRAFWT and CRAFWT with IC50s of 5.8, 9.1 and 15 nM, respectively.
| Name | N-(3,3-Dimethylbutyl)-N'-[2-fluoro-4-methyl-5-[7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl]phenyl]urea |
|---|---|
| Synonyms |
Urea, N-(3,3-dimethylbutyl)-N'-[2-fluoro-4-methyl-5-[7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl]phenyl]-
dp 4978 ly 3009120 1-(3,3-Dimethylbutyl)-3-{2-fluoro-4-methyl-5-[7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl]phenyl}urea LY-3009120 LY3009120 |
| Description | LY3009120 is a pan RAF inhibitor which inhibits BRAFV600E, BRAFWT and CRAFWT with IC50s of 5.8, 9.1 and 15 nM, respectively. |
|---|---|
| Related Catalog | |
| Target |
BRafV600E:5.8 nM (IC50) Braf:9.1 nM (IC50) CRAF:15 nM (IC50) |
| In Vitro | In the whole-cell based KiNativ assay, LY3009120 shows affinity to each RAF isoform with the IC50 of 44, 31-47 and 42 nM for ARAF, BRAF and CRAF respectively. LY3009120 exhibits anti-proliferative effects on cell lines harboring BRAFV600E, KRASG13 and KRASG12 mutations. LY3009120 (1 μM) inhibits the phosphorylation of both MEK1/2 and ERK1/2 in cell lines with high basal levels of pMEK1/2 and pERK1/2 (RKO and HCT 116)[1]. LY3009120 shows inhibitory effect on tumor cells such as BxPC-3, NCI-H2405 and OV-90 cell lines. LY3009120 (0.01 μM) demonstrates potent and dose-dependent inhibition of phospho-MEK and ERK in all three cell lines. LY3009120 demonstrates a concentration-dependent cell growth inhibition with IC50 values of 0.04, 0.087, and 0.007 μM against H2405, BxPC-3, and OV-90 cells, respectively[2]. LY3009120 inhibits BRAFWT, CRAFWT, BRAFV600E, and BRAFV600E+G468A with the IC50 values of 9.1, 15, 5.8, and 17 nM, respectively. LY3009120 induces BRAF-CRAF dimerization but inhibits the phosphorylation of downstream MEK and ERK. LY3009120 also inhibits various forms of RAF dimers including BRAF or CRAF homodimers[3]. LY3009120 gives only very minor activation at very low doses, with near complete inhibition of phospho-ERK at concentrations above 100 nM[4]. |
| In Vivo | LY3009120 (20 mg/kg bid) displays significant activity in in vivo BRAFmut and KRASmut CRC xenograft models. In Colo 205 xenografts (BRAFmut), LY3009120 results in statistically significant tumor regression, while treatment of HCT 116 xenografts (KRASmut) results in statistically significant inhibition of tumor growth. LY3009120 treatment reduces pMEK1/2 in all HT-29 xenografts and reduces pERK1/2 in the majority of HT-29 xenografts[1]. LY3009120 (15 or 30 mg/kg) achieves almost complete tumor growth regression, and inhibits downstream phospho-MEK and ERK by approximately 70% and 60%, respectively, in the H2405 model[2]. |
| Kinase Assay | In the BRAF WT enzymatic assay, the reaction mixture contains 1.2 nM BRAF, 30 nM MEK1, 1000 µM ATP, 3.5 units (per 100 µL) of PK, 5 units (per 100 µL) of LDH, 1 mM PEP, and 280 µM of NADH. In the CRAF assay, the reaction mixture contains 0.6 nM CRAF, 26 nM MEK1, 2000 µM ATP, and the same amount of PK, LDH, PEP and NADH. In the BRAFV600E assay, the reaction mixture contains 1.6 µM BRAFV600E, 26 nM MEK1, 200 µM ATP and the same amount of PK, LDH, PEP and NADH as above. In the BRAFV600E+G468A assay, the reaction mixture contains 3.5 nM BRAF, 30 nM MEK1, 200 µM ATP and the same amount of PK, LDH, PEP and NADH as above. All assays are started by mixing the above mixture with test compound and monitored at A340 continuously for approximately 5 hr. Reaction data at the 3 to 4 hour time frame are collected to calculate IC50. |
| Cell Assay | Briefly, cells are grown in McCoy’s 5A supplemented with 10% characterized fetal bovine serum and 1% penicillin/streptomycin/l-glutamine at 37°C, 5% CO2, and 95% humidity. Cells are allowed to expand until 75-90% confluency at which point they are subcultured or harvested for assay use. A serial dilution of test compound is dispensed into a 384-well black clear bottom plate in triplicate. Six-hundred-twenty-five cells are added per well in 50 μL of complete growth medium in the 384-well plate. Plates are incubated for 67 h at 37°C, 5% CO2, and 95% humidity. At the end of the incubation period, 10 μL of a 440 μM solution of resazurin in PBS is added to each well of the plate and plates are incubated for an additional 5 h at 37°C, 5% CO2, and 95% humidity. Plates are read on a Synergy2 reader using an excitation of 540 nm and an emission of 600 nm. Data are analyzed using Prism softwareto calculate IC50 values. |
| Animal Admin | Briefly, 5×106 to 10×106 tumor cells in a 1:1 Matrigel mix (0.2 mL total volume) are injected subcutaneously into the right hind flank of female NIH nude rats. After tumors reach a desired size of approximately 300 mm3, animals are randomized into groups of 8 for efficacy studies. Drugs (LY3009120 or vemurafenib) are administered orally (gavage) in 0.6-mL volume of vehicle with the dose schedules. Tumor growth and body weight are monitored over time to evaluate efficacy and signs of toxicity. |
| References |
| Density | 1.2±0.1 g/cm3 |
|---|---|
| Molecular Formula | C23H29FN6O |
| Molecular Weight | 424.514 |
| Exact Mass | 424.238678 |
| PSA | 91.83000 |
| LogP | 3.88 |
| Index of Refraction | 1.623 |
| Storage condition | -20℃ |