CCT245737 (C09-0823-247)

InformationCCT245737 (SRA737, PNT-737) is an orally activeCHK1inhibitor with The IC50 of 1.4 nM. It exhibits >1,000-fold selectivity against CHK2 and CDK1.TargetsChk1 (Cell-free assay) 1.4 nMIn vitroCCT245737 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 vivoMouse 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 Incubation Time：96 h. Specifications and Purity: 99%. Molecular Formula: C16H16F3N7O. Molecular Weight: 379.34. PubChem CID: 72165232. Isomeric SMILES: C1CO[C@H](CN1)CNC2=CC(=NC=C2C(F)(F)F)NC3=NC=C(N=C3)C#N.