LY3009120
(Synonyms: DP-4978) 目录号 : GC13980
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。
Cas No.:1454682-72-4
Sample solution is provided at 25 µL, 10mM.
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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.
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. |
|
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. |
|
Reaction Conditions |
LY3009120 (0.5 μM) for 24h/48h |
|
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. |
|
Dosage form |
20-30mg/kg LY3009120 twice daily ( orally) |
|
Applications |
LY3009120 treatment reduced pMEK1/2 in all HT-29 xenografts and reduced pERK1/2 in the majority of HT-29 xenografts. |
|
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. |
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| Cas No. | 1454682-72-4 | SDF | |
| 别名 | DP-4978 | ||
| 化学名 | 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(2-methyl-7-(methylamino)pyrido[2,3-d]pyrimidin-3-yl)phenyl)urea | ||
| Canonical SMILES | CC1=NC2=NC(NC)=NC=C2C=C1C3=CC(NC(NCCC(C)(C)C)=O)=C(F)C=C3C | ||
| 分子式 | C23H29FN6O | 分子量 | 424.51 |
| 溶解度 | ≥ 4.25mg/mL in DMSO with ultrasonic and warming | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.3557 mL | 11.7783 mL | 23.5566 mL |
| 5 mM | 0.4711 mL | 2.3557 mL | 4.7113 mL |
| 10 mM | 0.2356 mL | 1.1778 mL | 2.3557 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet