LY3009120

LY3009120 is an inhibitor of Raf kinases, including A-Raf, B-Raf, and c-Raf (IC₅₀s = 44, 31-47, and 42 nM, respectively, in whole cell lysates).^1,2 It also inhibits B-Raf mutants V600E and V600E+G468A (IC₅₀s = 5.8 and 17 nM, respectively, in biochemical assays).² LY3009120 induces Raf dimerization and, unlike vemurafenib (PLX4032; Item No. 10618) and dabrafenib (Item No. 16989), inhibits kinase activity of induced dimers.² It inhibits cell cycling in B-Raf or Ras mutant cancer cells and has significant antitumor activity in B-Raf and K-Ras mutant preclinical models of colorectal cancer.^2,3 LY3009120 is also active against B-Raf in-frame deletions in vitro and in mouse models.⁴

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1. Henry, J.R., Kaufman, N.D., Peng, S.-B., 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 tumor cells. J. Med. Chem. 58(10), 4165-4179 (2015).

2. Peng, S.-B., Henry, J.R., Kaufman, M.D., et al. Inhibition of RAF isoforms and active dimers by LY3009120 leads to anti-tumor activities in RAS or BRAF mutant cancers. Cancer Cell 28(3), 384-398 (2015).

3. Vakana, E., Pratt, S., Blosser, W., et al. LY3009120, a panRAF inhibitor, has significant anti-tumor activity in BRAF and KRAS mutant preclinical models of colorectal cancer. Oncotarget 8(6), 9251-9266 (2017).

4. Chen, S.-H., Zhang, Y., Van Horn, R.D., et al. Oncogenic BRAF deletions that function as homodimers and are sensitive to inhibition by RAF dimer inhibitor LY3009120. Cancer Discov. 6(3), 300-315 (2016).