LY3009120 (DP-4978) is a pan RAF inhibitor which inhibits BRAF^V600E, BRAF^WT and CRAF^WT with IC₅₀s of 5.8, 9.1 and 15 nM, respectively.

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 BRAF^V600E, KRAS^G13 and KRAS^G12 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 BRAF^WT, CRAF^WT, BRAF^V600E, and BRAF^V600E+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].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

LY3009120 (20 mg/kg bid) displays significant activity in in vivo BRAF^mut and KRAS^mut CRC xenograft models. In Colo 205 xenografts (BRAF^mut), LY3009120 results in statistically significant tumor regression, while treatment of HCT 116 xenografts (KRAS^mut) 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].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

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• [1]. Vakana E, et al. LY3009120, a panRAF inhibitor, has significant anti-tumor activity in BRAF and KRAS mutant preclinical models of colorectal cancer. Oncotarget. 2017 Feb 7;8(6):9251-9266  [Content Brief]

  [2]. Chen SH, et al. Oncogenic BRAF Deletions That Function as Homodimers and Are Sensitive to Inhibition by RAF Dimer Inhibitor LY3009120. Cancer Discov. 2016 Mar;6(3):300-15  [Content Brief]

  [3]. Peng SB, 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  [Content Brief]

  [4]. Henry JR, et al. Discovery of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a pan-RAF inhibitor with minimal paradoxical activation and activity against BRAF or RAS mutant tumo  [Content Brief]