Samuraciclib hydrochloride (ICEC0942 hydrochloride)

Samuraciclib hydrochloride (ICEC0942 hydrochloride, CT7001 hydrochloride) is a new, orally bioavailable CDK7 inhibitor with an IC50 of 40nM. The IC50 values for CDK1, CDK2, CDK5 and CDK9 were 45-, 15-, 230- and 30-fold higher. ICEC0942 (CT7001) promotes c

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货号: ajce49712
CAS: 1805789-54-1
别名: CT7001 hydrochloride; ICEC0942 hydrochloride
分子式: C22H31ClN6O
分子量: 430.97
纯度: >98%
溶解度: DMSO : ≥ 62.5 mg/mL (145.02 mM)
储存: Store at -20°C
库存: 现货

Background

A wide range of cancer types are sensitive to CDK7 inhibition by ICEC0942 with GI50 values ranging between 0.2-0.3 ?M. ICEC0942 inhibits PolII, CDK1, CDK2 and RB (retinoblastoma) phosphorylation in the MCF7 breast cancer cell line in a time and dose-sependent manner. ICEC0942 inhibits phosphorylation of CDK7 substrates and promotes cell cycle arrest and apoptosis[1].

In xenografts of both breast and colorectal cancers, ICEC0942 has substantial anti-tumor effects. For pharmacokinetics, CD1 male mice are treated intravenously (IV), subcutaneously (SC) or by oral gavage (PO) with 10 mg/kg ICEC0942. In plasma, ICEC0942 levels decline in a bi-phasic manner, indicating rapid distribution into tissues. Following IV administration of ICEC0942 at 10 mg/kg in male CD1 mice Cl(plasma) is calculated at 78 ml.min/kg. Blood/plasma ratio (Bl/Pl) is 1.81. ICEC0942 has a half-life of 1.9 hrs, a moderate half-life in this species. Only a small proportion (13.5%) of ICEC0942 is metabolized after 2 and 4 hour following a single PO administration (100 mg/kg). Comparing exposure (AUCt) after single PO and IV administration at 10 mg/kg, oral bioavailability (F%) is calculated at 30%. Median Tmax for PO administration is 2 hours and is unaffected by increasing dose. Over this dose range, Cmax is linearly associated with dose, as is the total exposure over time (AUCt). In tumor-bearing mice, there is appreciable accumulation of ICEC0942 in tumors 6-hours post administration. ICEC0942 levels in tumors lag behind plasma levels[1].

[1] Patel H, et al. Mol Cancer Ther. 2018, 17(6):1156-1166.

Protocol

Kinase experiment:

The purified recombinant CDK2/cycE1 and CDK7/CycH/MAT1 are used in the assay. Kinase assays are performed. Briefly, Rb-CTF and RNA Polymerase?II peptide is used for CDK2 and CDK7 kinase assays, respectively. A luciferase assay is used to determine ATP remaining at the end of the kinase reaction, which provides a measure of kinase activity. GraphPad Prism Software is used to generate the IC50 values for each CDK[1].

参考文献:

[1]. Hazel P, et al. Inhibitor Selectivity for Cyclin-Dependent Kinase?7: A?Structural, Thermodynamic, and Modelling Study. ChemMedChem. 2017 Mar 7;12(5):372-380.