CCT245737 (SRA737, PNT-737) is an orally active CHK1 inhibitor with The IC50 of 1.4 nM. It exhibits >1,000-fold selectivity against CHK2 and CDK1.
Storage Temp
Store at -20°C
Shipped In
Ice chest + Ice pads
Grade
Moligand™
Action Type
INHIBITOR
Mechanism of action
Inhibitor of checkpoint kinase 1;Inhibitor of checkpoint kinase 2
Product Description
Information
CCT245737 (SRA737, PNT-737) is an orally activeCHK1inhibitor with The IC50 of 1.4 nM. It exhibits >1,000-fold selectivity against CHK2 and CDK1.
Targets
Chk1 (Cell-free assay) 1.4 nM
In vitro
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.
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.
Cell Research(from reference)
Cell lines：The colon tumor cell lines HT29 and SW620, the pancreatic cancer cell line MiaPaCa-2 and the non-small cell lung cancer Calu6 cell line
1.Walton MI, Eve PD, Hayes A, Henley AT, Valenti MR, De Haven Brandon AK, Box G, Boxall KJ, Tall M, Swales K et al.. (2016) The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eµ-MYC driven B-cell lymphoma.. Oncotarget, 7 (3):(2329-42). [PMID:26295308]
2.Osborne JD, Matthews TP, McHardy T, Proisy N, Cheung KM, Lainchbury M, Brown N, Walton MI, Eve PD, Boxall KJ et al.. (2016) Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737).. J Med Chem, 59 (11):(5221-37). [PMID:27167172]
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I2220352