LY3009120 (Synonyms: DP-4978)

LY3009120 is a pan-RAF and RAF dimer inhibitor that inhibits all RAF isoforms and occupies both protomers in RAF dimers. LY3009120 bound ARAF, BRAF, and CRAF native proteins with IC50 values of 44, 31-47, and 42 nM, respectively. LY3009120 induces BRAF-CRAF dimerization but inhibits the phosphorylation of downstream MEK and ERK, suggesting that it effectively inhibits the kinase activity of BRAF-CRAF heterodimers^[1,7].

Treatment of both BRAFmut and KRASmut CRC cell lines with LY3009120 induced an increase in the percentage of cells in G1, indicative of G1 cell cycle arrest, with significant debris accumulation (sub-G1 population) in the HCT 116 and Colo 205 cell lines^[2]. LY3009120 has an anti adipogenic effect on 3T3 L1 cells ^[3]. LY3009120 suppressed BRAF-related downstream pathway molecules and induced cleavage of poly ADP-ribose polymerase in all examined NSCLC cell lines. LY3009120 also inhibited in vivo tumor growth in NSCLC cells harboring the BRAF non-V600E mutation^[4].

LY3009120 treatment reduced pMEK1/2 in all HT-29 xenografts and reduced pERK1/2 in the majority of HT-29 xenografts while LY3009120 had unremarkable effects on the phosphorylation of MEK1/2 and ERK1/2 in the Colo 320HSR xenograft model at a 50% increased dose^[2]. In vivo, LY3009120 significantly alleviated dextran sulfate sodium (DSS)-induced colitis as indicated by prevention of body weight loss, colon shortening, and decreased mortality^[5]. Combinatory treatment with LY3009120 and abemaciclib synergistically inhibited proliferation of tumor cells in vitro and led to tumor growth regression in xenograft models with a KRAS, NRAS or BRAF mutation at the doses of two drugs that were well tolerated in combination^[6].

References:
[1]. Henry JR, Kaufman MD, 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. 2015 May 28;58(10):4165-79. doi: 10.1021/acs.jmedchem.5b00067. Epub 2015 May 12. PMID: 25965804.
[2]. Vakana E, Pratt S, 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. doi: 10.18632/oncotarget.14002. PMID: 27999210; PMCID: PMC5354729.
[3]. Yang SM, Park YK, et,al. LY3009120, a pan-Raf kinase inhibitor, inhibits adipogenesis of 3T3-L1 cells by controlling the expression and phosphorylation of C/EBP-α, PPAR-γ, STAT?3, FAS, ACC, perilipin A, and AMPK. Int J Mol Med. 2018 Dec;42(6):3477-3484. doi: 10.3892/ijmm.2018.3890. Epub 2018 Sep 21. PMID: 30272260.
[4]. Miyauchi S, Shien K, et,al. Antitumor Effects of Pan-RAF Inhibitor LY3009120 Against Lung Cancer Cells Harboring Oncogenic BRAF Mutation. Anticancer Res. 2020 May;40(5):2667-2673. doi: 10.21873/anticanres.14237. PMID: 32366411.
[5]. Zhang C, Luo Y, et,al. A pan-RAF inhibitor LY3009120 inhibits necroptosis by preventing phosphorylation of RIPK1 and alleviates dextran sulfate sodium-induced colitis. Clin Sci (Lond). 2019 Apr 16;133(8):919-932. doi: 10.1042/CS20181081. PMID: 30944150.
[6]. Chen SH, Gong X, et,al. RAF inhibitor LY3009120 sensitizes RAS or BRAF mutant cancer to CDK4/6 inhibition by abemaciclib via superior inhibition of phospho-RB and suppression of cyclin D1. Oncogene. 2018 Feb 8;37(6):821-832. doi: 10.1038/onc.2017.384. Epub 2017 Oct 23. PMID: 29059158.
[7]. Peng SB, Henry JR, 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. doi: 10.1016/j.ccell.2015.08.002. Epub 2015 Sep 3. PMID: 26343583.