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MSC2530818
本产品不向个人销售,仅用作科学研究,不用于任何人体实验及非科研性质的动物实验。
MSC2530818图片
CAS NO:1883423-59-3
规格:≥98%
包装与价格:
包装价格(元)
5mg电议
10mg电议
25mg电议
50mg电议
100mg电议
250mg电议
500mg电议

产品介绍
理化性质和储存条件
Molecular Weight (MW) 340.81
Formula C18H17ClN4O
CAS No. 1883423-59-3
Storage-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)DMSO:> 70 mg/mL
Water: <1 mg/mL
Ethanol: > 70 mg/mL
Chemical Name [(2S)-2-(4-Chlorophenyl)pyrrolidin-1-yl]-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methanone
Synonyms MSC-2530818; MSC2530818; MSC 2530818
SMILES Code O=C(N1[C@H](C2=CC=C(Cl)C=C2)CCC1)C3=CN=C(NN=C4C)C4=C3
实验参考方法
In Vitro

In vitro activity: MSC2530818 is novel, potent, selective and orally available small molecule inhibitor of cyclin dependent kinase CDK8 with the IC50 of 2.6 nM. It demonstrates excellent pharmacokinetics and pharmacodynamics including good kinase selectivity, high biochemical and cellular potency, microsomal stability, and reasonable oral bioavailability. 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. MSC2530818 was identified in a high-throughput screening campaign and further progressed by structure-based design. MSC2530818 demonstrated suitable potency and selectivity to progress into preclinical in vivo efficacy and safety studies.


Kinase Assay: MSC2530818 is novel, potent, selective and orally available small molecule inhibitor of cyclin dependent kinase CDK8 with the IC50 of 2.6 nM.


Cell Assay: SC2530818 demonstrates potent inhibition of WNT-dependent transcription in human cancer cell lines that have constitutively activated WNT signaling. For example, MSC2530818 inhibits the reporter-based luciferase readout in several cell lines bearing activating WNT-pathway mutations; LS174T (β-catenin mutant, IC50=32±7 nM), COLO205 (APC mutant, IC50=9±1 nM) and demonstrates inhibition of WNT3a ligand-dependent reporter readout in PA-1 cells (IC50=52±30 nM). MSC2530818 demonstrates minimal activity in the CEREP panel, being active on the dopamine transporter (IC50=8.5 μM) as the only activity below 10 μM, and demonstrates minimal hERG inhibition. Furthermore, MSC2530818 is a soluble CDK8 inhibitor with high permeability and low efflux ratio in Caco-2 cells and does not inhibit any cytochrome P450 subtypes.

In VivoTumor-bearing mice treated with MSC2530818 shows reduction in tumor growth with T/C ratios (based on final tumor weights) of 49% and 57%, respectively. MSC2530818 is generally well tolerated, with no effects on mouse body weight in the qd administration schedule and manageable body weight loss. The human clearance and volume of distribution at steady-state are estimated to be low (0.14 L/h/kg) and small (0.48 L/kg), respectively, resulting in a short predicted terminal half-life (2.4 h). Physiologically based pharmacokinetics simulations suggested that human oral bioavailability may be ≥75% up to dose level of 500 mg daily
Animal modelNCr athymic mice
Formulation & DosagePrepared in kolliphor 20% w/v in water; 50 mg/kg bid or 100 mg/kg qd; oral gavage
References J Med Chem. 2016 Oct 27;59(20):9337-9349.