LY3009120

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

LY3009120 (DP-4978) 是一种有效的泛 RAF 和 RAF 二聚体抑制剂，对 BRAF V600E、BRAF WT 和 CRAF WT 的 IC50 分别为 5.8、9.1 和 15 nM。

LY3009120 (DP-4978) is a potent pan-RAF and RAF dimer inhibitor with IC50 of 5.8, 9.1 and 15 nM for BRAF V600E, BRAF WT and CRAF WT, respectively; inhibits ARAF, BRAF, and CRAF isoforms with similar affinity (4, 31-47 and 42 nM for ARAF, BRAF and CRAF), induces BRAF-CRAF dimerization but inhibits the phosphorylation of downstream MEK and ERK, also inhibits various forms of RAF dimers including BRAF or CRAF homodimers; exhibits anti-proliferative effects on cell lines harboring BRAF V600E, KRAS G13 and KRAS G12 mutations, inhibits cell growth of H2405, BxPC-3, and OV-90 cells (IC50=0.04, 0.087, and 0.007 uM); displays significant activity in in vivo BRAF mut and KRAS mut CRC xenograft models.Skin Cancer Phase 1 Clinical(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). 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. 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. LY3009120 gives only very minor activation at very low doses, with near complete inhibition of phospho-ERK at concentrations above 100 nM. (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. 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.

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). 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. 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. LY3009120 gives only very minor activation at very low doses, with near complete inhibition of phospho-ERK at concentrations above 100 nM.

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. 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.

DP-4978 | LY-3009120

MAPK/ERK Signaling

Raf

B-Raf(V600E)|B-Raf(WT)|C-Raf|VEGFR2?(KDR)

Cancer

Skin Cancer

1454682-72-4

424.5144

C23H29FN6O

>98% (HPLC)

DMSO: ≥ 38 mg/mL

O=C(NC1=CC(C2=CC3=CN=C(NC)N=C3N=C2C)=C(C)C=C1F)NCCC(C)(C)C

Urea, N-(3,3-dimethylbutyl)-N'-[2-fluoro-4-methyl-5-[7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl]phenyl]-

(-20℃)

With Ice Pack

≥ 2 years