product name CCT245737
Description: CCT245737 is a novel, potent, ATP-competitive CHK1 inhibitor with an IC50 of 30-220 nM. target:CHK1; IC 50: 30-220nM; It shows <50% inhibition at 10 μM for 85/121 kinases, representing a selectivity for CHK1 inhibition of >5000-fold over these enzymes. CCT245737 enhanced gemcitabine antitumor activity to a greater degree than for higher doses of either agent alone, without increasing toxicity. CCT2457374 shows an increase in plasma and tumoconcentrations between 3-100 mg/kg.
References: Oncotarget. 2016 Jan 19;7(3):2329-42.
379.34
Formula
C16H16F3N7O
CAS No.
1489389-18-5
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 75 mg/mL (197.7 mM)
Water: <1 mg/mL
Ethanol: 9 mg/mL (23.7 mM)
Solubility (In vivo)
Synonyms
CCT 245737; CCT-245737
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19406925
| In Vitro |
In vitro activity: CCT245737 is a potent inhibitor of recombinant human CHK1 with IC50 of 1.4±0.3 nM (mean±SD, n = 3, EZ Reader II assay). There is > 1,000-fold selectivity for CHK1 versus the functionally important kinases CDK1 and CHK2 (IC50=1.26-2.44 and 9.03 μM, respectively), and at least a 90-fold selectivity against cross-reacting kinases such as ERK8, PKD1, RSK1 and 2. CCT245737 potently inhibits cellular CHK1 activity (IC50 30-220nM) and enhances gemcitabine and SN38 cytotoxicity in multiple human tumor cell lines and human tumor xenograft models. It can abrogate an etoposide-induced G2/M arrest. CCT245737 has high cell permeability, as measured by transport across a CaCo2 cell monolayer. Kinase Assay: CCT245737 shows <50% inhibition at 10 μM for 85/121 kinases, representing a selectivity for CHK1 inhibition of >5000-fold over these enzymes. Cell Assay: Cytotoxicity is determined as the drug concentration that gave 50% inhibition of tumor cell proliferation (GI50) using a 96h (i.e. 4-doublings) Sulforhodamine B (SRB) assay. Inhibition of intracellular CHK1 activity is measured using a cell based ELISA for the abrogation of an etoposide induced G2 checkpoint (mitosis induction assay, MIA). |
|---|---|
| In Vivo | Mouse oral bioavailability is complete (100%) with extensive tumor exposure. CCT245737 shows significant single-agent activity against a MYC-driven mouse model of B-cell lymphoma. An i.v. dose of 10mg/kg CCT245737 into BALB/c mice gives a peak plasma concentration of 4μmol/L, with a half-life of 2.86h, an AUC0-∞ of 9.96μmol.h/L, a plasma clearance of 2.1L/h/kg and a large volume of distribution (0.19L). The equivalent oral dose gave an almost identical profile with an AUC0-∞ of 10.4μmol.h/L showing complete oral bioavailability (F = 105%). In a word, CCT245737 shows complete oral bioavailability with linear pharmacokinetics and high tumor/plasma ratios consistent with extensive tumor exposure. Adequate CCT245737 tumor drug exposure takes a significant antitumor activity. |
| Animal model | BALB/c mice |
| Formulation & Dosage | Dissolved in DPTW (10% DMSO, 20% PEG400, 5% Tween 80 and 65% water) for oral vehicle; 10mg/kg(i.v.); 150mg/kg(p.o.); i.v. or p.o. |
| References | Oncotarget. 2016 Jan 19;7(3):2329-42. |
