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

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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, KRAS and KRAS 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 BRAF, CRAF, BRAF, and BRAF 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.

Medlife 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 and KRAS CRC xenograft models. In Colo 205 xenografts (BRAF), LY3009120 results in statistically significant tumor regression, while treatment of HCT 116 xenografts (KRAS) 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.

Medlife 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  [Information]

  [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  [Information]

  [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  [Information]

  [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  [Information]

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