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].
参考文献:
[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.
LY3009120 是一种泛 RAF 和 RAF 二聚体抑制剂，可抑制所有 RAF 亚型并占据 RAF 二聚体中的两个原聚体。 LY3009120 结合 ARAF、BRAF 和 CRAF 天然蛋白，IC50 值分别为 44、31-47 和 42 nM。 LY3009120诱导BRAF-CRAF二聚化但抑制下游MEK和ERK的磷酸化，表明它有效抑制BRAF-CRAF异源二聚体的激酶活性[1,7]。
用 LY3009120 处理 BRAFmut 和 KRASmut CRC 细胞系诱导 G1 细胞百分比增加，表明 G1 细胞周期停滞，在 HCT 116 和 Colo 205 细胞中有显着的碎片积累（亚 G1 细胞群）行[2]。 LY3009120 对 3T3 L1 细胞具有抗脂肪形成作用[3]。 LY3009120 在所有检查的 NSCLC 细胞系中抑制 BRAF 相关的下游通路分子并诱导聚 ADP-核糖聚合酶的裂解。 LY3009120 还在携带 BRAF 非 V600E 突变的 NSCLC 细胞中抑制体内肿瘤生长[4]。
LY3009120 处理降低了所有 HT-29 异种移植物中的 pMEK1/2 并降低了大多数 HT-29 异种移植物中的 pERK1/2，而 LY3009120 对 Colo 320HSR 异种移植物模型中 MEK1/2 和 ERK1/2 的磷酸化没有显着影响剂量增加 50%[2]。在体内，LY3009120 显着减轻了葡聚糖硫酸钠 (DSS) 诱导的结肠炎，如防止体重减轻、结肠缩短和降低死亡率所示[5]。 LY3009120 和 abemaciclib 的联合治疗在体外协同抑制肿瘤细胞增殖，并导致具有 KRAS、NRAS 或 BRAF 突变的异种移植模型中的肿瘤生长消退，两种药物联合使用的剂量耐受性良好[6]< /sup>.
| Kinase experiment [1]: | |
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Preparation Method |
To confirm compound 13 as a pan-RAF inhibitor, it was evaluated in a whole cell-based KiNativ assay developed. LY3009120 was incubated with A375 whole cell lysate for 15 min, and the binding affinities of over 170 kinases were determined by direct competitive binding with an ATP analog. |
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Applications |
LY3009120 bound ARAF, BRAF, and CRAF native proteins with IC50 values of 44, 31-47, and 42 nM, respectively. |
| Cell experiment [2]: | |
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Cell lines |
CRC cell lines |
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Preparation Method |
CRC cell lines treated with either DMSO or LY3009120 (0.5 μM) for the times indicated, fixed and stained with propidium iodide and analyzed for cell cycle by flow cytometry. |
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Reaction Conditions |
LY3009120 (0.5 μM) for 24h/48h |
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Applications |
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. |
| Animal experiment [3]: | |
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Animal models |
Female NIH nude rats |
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Preparation Method |
5 million tumor cells in inoculation media were implanted subcutaneously in the right hind flank of female NIH nude rats. When tumors reached ~400 mm3, animals were randomized into groups of 8 10 and treated as indicated in the respective figure legends. LY3009120 was administered orally and animals were monitored for toxicity. |
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Dosage form |
20-30mg/kg LY3009120 twice daily ( orally) |
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Applications |
LY3009120 treatment reduced pMEK1/2 in all HT-29 xenografts and reduced pERK1/2 in the majority of HT-29 xenografts. |
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参考文献: [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. |
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