Home>>Signaling Pathways>> DNA Damage/DNA Repair>> CDK>>MSC2530818

MSC2530818 Sale

目录号 : GC32746

A Cdk8 inhibitor

MSC2530818 Chemical Structure

Cas No.:1883423-59-3

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥1,385.00
现货
5mg
¥1,260.00
现货
10mg
¥2,025.00
现货
25mg
¥4,320.00
现货
50mg
¥7,020.00
现货
100mg
¥13,646.00
现货

电话:400-920-5774 Email: sales@glpbio.cn

Customer Reviews

Based on customer reviews.

Sample solution is provided at 25 µL, 10mM.

产品文档

Quality Control & SDS

View current batch:

实验参考方法

Animal experiment:

Mice: MSC2530818 is then assessed in an established SW620 human colorectal cancer xenograft model in female NCr athymic mice. Tumor-bearing mice are treated orally with MSC2530818 (50 mg/kg bid or 100 mg/kg qd) for 16 days. Tumor weights are measured and body weights are monitored[1].

References:

[1]. Czodrowski P, et al. Structure-Based Optimization of Potent, Selective, and Orally Bioavailable CDK8 Inhibitors Discovered by High-Throughput Screening. J Med Chem. 2016 Oct 27;59(20):9337-9349.

产品描述

MSC2530818 is an orally bioavailable cyclin-dependent kinase 8 (Cdk8) inhibitor (IC50 = 2.6 nM).1 It is selective for Cdk8 over a panel of 264 kinases at 1 ?M but does inhibit glycogen synthase kinase 3α (GSK3α; IC50 = 691 nM). MSC2530818 inhibits STAT1 phosphorylation in SW620 colorectal cancer cells with an IC50 value of 8 nM. It also inhibits Wnt-dependent transcription in LS 174T, COLO 205, and PA-1 cancer cells (IC50s = 32, 9, and 52 nM, respectively, in luciferase reporter assays). MSC2530818 (50 and 100 mg/kg) reduces tumor growth in a SW620 mouse xenograft model.

1.Czodrowski, P., Mallinger, A., Wienke, D., et al.Structure-based optimization of potent, selective, and orally bioavailable CDK8 inhibitors discovered by high-throughput screeningJ. Med. Chem.59(20)9337-9349(2016)

Chemical Properties

Cas No. 1883423-59-3 SDF
Canonical SMILES O=C(N1[C@H](C2=CC=C(Cl)C=C2)CCC1)C3=CN=C(NN=C4C)C4=C3
分子式 C18H17ClN4O 分子量 340.81
溶解度 DMSO : ≥ 125 mg/mL (366.77 mM) 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。
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。

溶解性数据

制备储备液
1 mg 5 mg 10 mg
1 mM 2.9342 mL 14.6709 mL 29.3419 mL
5 mM 0.5868 mL 2.9342 mL 5.8684 mL
10 mM 0.2934 mL 1.4671 mL 2.9342 mL
  • 摩尔浓度计算器

  • 稀释计算器

  • 分子量计算器

质量
=
浓度
x
体积
x
分子量
 
 
 
*在配置溶液时,请务必参考产品标签上、MSDS / COA(可在Glpbio的产品页面获得)批次特异的分子量使用本工具。

计算

动物体内配方计算器 (澄清溶液)

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
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

Research Update

Systemic Toxicity Reported for CDK8/19 Inhibitors CCT251921 and MSC2530818 Is Not Due to Target Inhibition

Cells 2019 Nov 9;8(11):1413.PMID:31717492DOI:10.3390/cells8111413.

CDK8/19 kinases, which mediate transcriptional reprogramming, have become an active target for cancer drug discovery. Several small-molecule CDK8/19 inhibitors showed in vivo efficacy and two have entered clinical trials, with no significant toxicities reported. However, Clarke et al. (eLife 2016; 5; e20722) found severe systemic toxicity associated with two potent CDK8/19 inhibitors, Cmpd3 (CCT251921) and Cmpd4 (MSC2530818), and suggested that their toxicity was due to on-target effects. Here, we compared five CDK8/19 inhibitors: Cmpd3, Cmpd4, Senexin B, 16-didehydro-cortistatin A (dCA) and 15w, in different assays. Only Cmpd4 showed striking toxicity in developing zebrafish. In cell-based assays for CDK8 and CDK19 inhibition, Cmpd3, Cmpd4, dCA and 15w showed similar low-nanomolar potency and efficacy against CDK8 and CDK19, while Senexin B was less potent. Only dCA produced sustained inhibition of CDK8/19-dependent gene expression. While toxicity of different compounds did not correlate with their effects on CDK8 and CDK19, kinome profiling identified several off-target kinases for both Cmpd3 and Cmpd4, which could be responsible for their toxicity. Off-target activities could have been achieved in the study of Clarke et al. due to high in vivo doses of Cmpd3 and Cmpd4, chosen for the ability to inhibit STAT1 S727 phosphorylation in tumor xenografts. We show here that STAT1 S727 phosphorylation is induced by various cytokines and stress stimuli in CDK8/19-independent manner, indicating that it is not a reliable pharmacodynamic marker of CDK8/19 activity. These results illustrate the need for careful off-target analysis and dose selection in the development of CDK8/19 inhibitors.

Development of Highly Potent and Selective Pyrazolopyridine Inhibitor of CDK8/19

ACS Med Chem Lett 2021 Oct 22;12(11):1689-1693.PMID:34795857DOI:10.1021/acsmedchemlett.1c00300.

CDK8 and its paralog CDK19 are cyclin-dependent kinases that are core components of the so-called Mediator complex that has essential roles as a positive and negative regulator of gene expression. Several efforts to develop inhibitors have yielded natural and synthetic ATP-competitive compounds including cortistatin A, Sel120, BCD-115, CCT251921 (1), and MSC2530818 (2). Here, we used a hybridization approach starting from CCT251921 and MSC2530818 to derive new inhibitors with the aim of developing highly potent and selective inhibitors of CDK8/19. Initial compounds suffered from rapid aldehyde oxidase-mediated metabolism. This liability was overcome by utilizing a pyrazolopyridine hinge binder with a chlorine at the C-3 position. These efforts resulted in JH-XVI-178 (compound 15), a highly potent and selective inhibitor of CDK8/19 that displays low clearance and moderate oral pharmacokinetic properties.

Structure-Based Optimization of Potent, Selective, and Orally Bioavailable CDK8 Inhibitors Discovered by High-Throughput Screening

J Med Chem 2016 Oct 27;59(20):9337-9349.PMID:27490956DOI:10.1021/acs.jmedchem.6b00597.

The mediator complex-associated cyclin dependent kinase CDK8 regulates β-catenin-dependent transcription following activation of WNT signaling. Multiple lines of evidence suggest CDK8 may act as an oncogene in the development of colorectal cancer. Here we describe the successful optimization of an imidazo-thiadiazole series of CDK8 inhibitors that was identified in a high-throughput screening campaign and further progressed by structure-based design. In several optimization cycles, we improved the microsomal stability, potency, and kinase selectivity. The initial imidazo-thiadiazole scaffold was replaced by a 3-methyl-1H-pyrazolo[3,4-b]-pyridine which resulted in compound 25 (MSC2530818) that displayed excellent kinase selectivity, biochemical and cellular potency, microsomal stability, and is orally bioavailable. Furthermore, we demonstrated modulation of phospho-STAT1, a pharmacodynamic biomarker of CDK8 activity, and tumor growth inhibition in an APC mutant SW620 human colorectal carcinoma xenograft model after oral administration. Compound 25 demonstrated suitable potency and selectivity to progress into preclinical in vivo efficacy and safety studies.