CCT244747 is a CHK1 inhibitor (IC50: 7.7 nM) and also abrogates G2 checkpoint (IC50: 29 nM).

Chk1:7.7 nM

CCT244747 demonstrates selective inhibition potential, performing poorly against CHK2 and CDK1 with IC50 values above 10 μM, whereas it more effectively inhibits FLT3 with an IC50 of 600 nM. It also significantly inhibits CHK1 cellular function, showing IC50s between 29 nM and 170 nM across various cell lines including HT29, SW620, MiaPaCa-2, and Calu6, with GI50s ranging from 0.33 μM to 3 μM. At a concentration of 0.3 μM, CCT244747 blocks CHK1 activity induced by SN38 and gemcitabine in HT29 and SW620 colon cancer lines, which leads to bypassing cell cycle arrest, alongside DNA damage and apoptosis induction. It exhibits robust inhibition (>80%) against a range of enzymes such as CHK1, RSK1, RSK2, AMPK, BRSK1, IRAK1, and TrkA. Additionally, CCT244747 enhances the sensitivity of bladder and head and neck cancer cells to radiation at concentrations between 0.5 and 2.0 μM and overcomes genotoxic-induced S and G2 arrest in colon cancer cell lines at 0.5 μM. At higher concentrations (10 μM), it shows less than 25% inhibition towards a spectrum of ion channels, including hNav1.5, hKv4.3/hKChIP2, hCav1.2, hKv1.5, hKCNQ1/hminK, and hHCN4.

CCT244747, administered orally at doses ranging from 100 to 300 mg/kg, effectively inhibits the gemcitabine-induced phosphorylation of CHK1 at S296 for up to 24 hours in HT29 colon tumor xenografts. At a dosage of 75 mg/kg, CCT244747 enhances the antitumor effects of gemcitabine in both HT29 colon tumor and Calu6 human lung cancer xenografts. A regimen of CCT244747 at 100 mg/kg once daily for 7 days significantly reduces tumor burden in various human tumor xenografts. Additionally, at a dose of 100 mg/kg, CCT244747 demonstrates radiosensitization activity in Cal27 xenografts. When administered at 150 mg/kg, CCT244747 also exhibits potent antitumor activity in combination with irinotecan in SW620 human colon tumor xenografts.