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LY3009120 Sale

(Synonyms: DP-4978) 目录号 : GC13980

A pan-Raf and Raf dimer inhibitor

LY3009120 Chemical Structure

Cas No.:1454682-72-4

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实验参考方法

Kinase experiment [1]:

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]:

Cell lines

CRC cell lines

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]:

Animal models

Female NIH nude rats

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.

产品描述

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>.

Chemical Properties

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
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1 mM 2.3557 mL 11.7783 mL 23.5566 mL
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Research Update

Pan-RAF inhibitor LY3009120 is highly synergistic with low-dose cytarabine, but not azacitidine, in acute myeloid leukemia with RAS mutations

Oncol Lett2021 Nov;22(5):745.PMID: 34539849DOI: 10.3892/ol.2021.13006

Alterations in RAS oncogenes have been implicated in various types of cancer, including acute myeloid leukemia (AML). Considering that currently, there are no targeted therapies for patients with RAS-mutated AML despite the poor outcomes, RAF may be a potential target for AML. In this study, we first analyzed the efficacy of different MAPK inhibitors in AML cell lines. We found that LY3009120, a pan-RAF inhibitor, significantly decreased cell survival in RAS-mutated AML cell lines. We then investigated the synergistic effects of LY3009120 with either cytarabine or azacitidine. We found that the combination of low-dose cytarabine and LY3009120 showed a synergistic effect in NRAS-mutated HL-60 cells and KRAS-mutated NB4 cells. This effect was caused by a decrease in proliferation, induction of apoptosis, and cell growth arrest through a decrease in phosphorylated MEK and ERK along with a cytotoxic response occurring specifically for the RAS mutation of the pan-RAF inhibitor LY3009120. In addition, we confirmed that combination treatment with low-dose cytarabine and LY3009120 led to an increase in apoptosis in primary AML cells. Our findings indicate that combination therapy with pan-RAF inhibitor LY3009120 and low-dose cytarabine may be a promising treatment strategy for RAS-mutated AML.

Antitumor Effects of Pan-RAF Inhibitor LY3009120 Against Lung Cancer Cells Harboring Oncogenic BRAF Mutation

Anticancer Res2020 May;40(5):2667-2673.PMID: 32366411DOI: 10.21873/anticanres.14237

Background/aim: The therapeutic strategy for patients with non-small-cell lung cancer (NSCLC) harboring the BRAF non-V600E mutation has not been established. LY3009120, a newly discovered pan-RAF inhibitor, has shown strong antitumor effects in cancers with various BRAF genotypes. This study investigated the antitumor effects of LY3009120 in NSCLC cells harboring the BRAF non-V600E mutation.
Materials and methods: We examined the antitumor effects of LY3009120 by MTS assay and flow cytometry. We analyzed the expression status of proteins by western blot. The mouse xenograft models were used for the in vivo experiments.
Results: 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.
Conclusion: LY3009120 is a potent therapeutic agent for patients with BRAF non-V600E mutant NSCLC.

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.PMID: 30944150DOI: 10.1042/CS20181081

A dramatic increase in the incidence of inflammatory bowel disease (IBD) has been observed in the past two decades, mainly in developed countries and also in developing regions. Necroptosis has been found to play an important role in the pathogenesis of IBD, suggesting its inhibitors are promising in clinic. However, clinical drugs targeting necroptosis are seriously lacking. Through screening a clinical compound library that contains 611 inhibitors, a pan-RAF inhibitor LY3009120 was found to be promising as a necroptosis inhibitor. LY3009120 inhibited necroptosis in vitro, and its inhibition against necroptosis was independent of its well-known activity to inhibit RAF. Surprisingly, LY3009120 prevented phosphorylation of receptor interacting serine/threonine kinase 1 (RIPK1) and subsequently phosphorylation of receptor interacting serine/threonine kinase 3 (RIPK3) and mixed lineage kinase domain like pseudokinase (MLKL) which happened during necroptosis. In vivo, LY3009120 significantly alleviated dextran sulfate sodium (DSS)-induced colitis as indicated by prevention of body weight loss, colon shortening, and decreased mortality. Furthermore, LY3009120 inhibited necroptosis of intestinal epithelial cells (IECs) and prevented intestinal barrier function loss. Consistently, LY3009120 decreased DSS-induced colonic inflammation, as indicated by decreased infiltration of macrophages and neutrophils, and decreased colonic TNF-¦Á, IL-6, and IL-1¦ level in DSS treated mice. These results indicate that an anti-cancer pan-RAF inhibitor LY3009120 is a necroptosis inhibitor and may serve as a potential therapeutic drug for colitis.

LY3009120, a pan-Raf kinase inhibitor, inhibits adipogenesis of 3T3-L1 cells by controlling the expression and phosphorylation of C/EBP-¦Á, PPAR-¦ì STAT?3, FAS, ACC, perilipin A, and AMPK

Int J Mol Med2018 Dec;42(6):3477-3484.PMID: 30272260DOI: 10.3892/ijmm.2018.3890

Excessive preadipocyte differentiation/adipogenesis is closely linked to the development of obesity. LY3009120 is a pan?Raf kinase inhibitor and is known for its anticancer activities. In the present study, the effect of LY3009120 on 3T3?L1 cell adipogenesis was investigated. The differentiation of 3T3?L1 preadipocytes into adipocytes was measured by Oil Red O staining and AdipoRed assay. Changes of cellular protein expression and phosphorylation levels in differentiating 3T3?L1 preadipocytes in the absence or presence of LY3009120 were determined by western blotting analysis. Cell count assay was used to assess the cytotoxicity of LY3009120 on 3T3?L1 cells. At 0.3 ?M, LY3009120 markedly inhibited lipid accumulation and decreased triglyceride content in differentiating 3T3?L1 cells. However, it had minimal effect on the elevated expression and phosphorylation of three Raf kinase isoforms (C?Raf, A?Raf, and B?Raf) observed in the cells. LY3009120 reduced not only the expression of CCAAT/enhancer?binding protein?¦Á (C/EBP?¦Á), peroxisome proliferator?activated receptor?¦à(PPAR?¦é, fatty acid synthase (FAS), acetyl CoA carboxylase (ACC), and perilipin A, but also reduced the phosphorylation of signal transducer and activator of transcription?3 (STAT?3) in differentiating 3T3?L1 cells. LY3009120 also increased the phosphorylation of adenosine 3',5'?cyclic monophosphate (cAMP)?activated protein kinase (AMPK), but did not affect the phosphorylation or expression of liver kinase B1 in these cells. In summary, this is the first report, to the best of our knowledge, demonstrating that LY3009120 has an anti?adipogenic effect on 3T3?L1 cells, which may be mediated through control of the expression and phosphorylation of C/EBP?¦Á, PPAR?¦ì STAT?3, FAS, ACC, perilipin A, and AMPK.

A Phase I Study of LY3009120, a Pan-RAF Inhibitor, in Patients with Advanced or Metastatic Cancer

Mol Cancer Ther2020 Feb;19(2):460-467.PMID: 31645440DOI: 10.1158/1535-7163.MCT-19-0681

Mutations in ERK signaling drive a significant percentage of malignancies. LY3009120, a pan-RAF and dimer inhibitor, has preclinical activity in RAS- and BRAF-mutated cell lines including BRAF-mutant melanoma resistant to BRAF inhibitors. This multicenter, open-label, phase I clinical trial (NCT02014116) consisted of part A (dose escalation) and part B (dose confirmation) in patients with advanced/metastatic cancer. In part A, oral LY3009120 was dose escalated from 50 to 700 mg twice a day on a 28-day cycle. In part B, 300 mg LY3009120 was given twice a day. The primary objective was to identify a recommended phase II dose (RP2D). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary efficacy. Identification of pharmacodynamic biomarkers was exploratory. In parts A and B, 35 and 16 patients were treated, respectively (N = 51). In part A, 6 patients experienced eight dose-limiting toxicities. The RP2D was 300 mg twice a day. Common (>10%) any-grade drug-related treatment-emergent adverse events were fatigue (n = 15), nausea (n = 12), dermatitis acneiform (n = 10), decreased appetite (n = 7), and maculopapular rash (n = 7). The median duration of treatment was 4 weeks; 84% of patients completed one or two cycles of treatment. Exposures observed at 300 mg twice a day were above the preclinical concentration associated with tumor regression. Eight patients had a best overall response of stable disease; there were no complete or partial clinical responses. Despite adequate plasma exposure levels, predicted pharmacodynamic effects were not observed.