| Identification | Back Directory | [Name]
(S)-(2-(4-chlorophenyl)pyrrolidin-1-yl)(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methanone | [CAS]
1883423-59-3 | [Synonyms]
CPD1540
MSC2530818
(S)-(2-(4-chlorophenyl)pyrrolidin-1-yl)(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methanone
[(2S)-2-(4-chlorophenyl)pyrrolidin-1-yl]-(3-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)methanone
Methanone, [(2S)-2-(4-chlorophenyl)-1-pyrrolidinyl](3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)- | [Molecular Formula]
C18H17ClN4O | [MDL Number]
MFCD31382190 | [MOL File]
1883423-59-3.mol | [Molecular Weight]
340.81 |
| Chemical Properties | Back Directory | [Boiling point ]
576.5±50.0 °C(Predicted) | [density ]
1.373±0.06 g/cm3(Predicted) | [storage temp. ]
Store at -20°C | [solubility ]
DMF: 30 mg/ml; DMF:PBS (pH 7.2) (1:1): 0.50 mg/ml; DMSO: 15 mg/ml; Ethanol: 10 mg/ml | [form ]
A crystalline solid | [pka]
9.65±0.40(Predicted) | [color ]
White to off-white |
| Hazard Information | Back Directory | [Description]
MSC2530818 is an orally bioavailable cyclin-dependent kinase 8 (Cdk8) inhibitor (IC50 = 2.6 nM). It is selective for Cdk8 over a panel of 264 kinases at 1 μM 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. | [Uses]
MSC2530818 is a potent, selective and orally available CDK8 inhibitor with an IC50 of 2.6 nM for CDK8. | [in vivo]
Tumor-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[1]. | [IC 50]
CDK8: 2.6 nM (IC50) | [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. DOI:10.1021/acs.jmedchem.6b00597 |
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