Description:

IC50: 29-170 nM

CHK1 is a serine/threonine kinase that is activated in response to single strand breaks (SSBs) in DNA caused by either direct DNA damage or replication stress. Activation of CHK1 initiates a signaling cascade culminating in cell cycle arrest leading to DNA repair, senescence or death. Inhibition of CHK1 abrogates cell cycle arrest, inhibits DNA repair and induces tumor cell death following DNA damage by a range of chemotherapeutic agents. CCT244747 is a potent and selective CHK1 inhibitor.

In vitro: CCT244747 inhibited cellular CHK1 activity, significantly enhanced the cytotoxicity of a few anticancer drugs and abrogated drug-induced S and G2 arrest in multiple tumor cell lines. Biomarkers of CHK1 activity and cell cycle inactivity were induced by genotoxics and inhibited by CCT244747, producing enhanced DNA damage and apoptosis [1].

In vivo: Active tumor concentrations of CCT244747 were obtained following oral administration. The antitumor activities of both gemcitabine and irinotecan were significantly enhanced by CCT244747 in human tumor xenografts, giving concomitant biomarker modulation indicative of CHK1 inhibition [1].

Clinical trial: Up to now, CCT244747 is still in the preclinical development stage.

Reference:
[1] Walton MI, Eve PD, Hayes A, Valenti MR, De Haven Brandon AK, Box G, Hallsworth A, Smith EL, Boxall KJ, Lainchbury M, Matthews TP, Jamin Y, Robinson SP, Aherne GW, Reader JC, Chesler L, Raynaud FI, Eccles SA, Collins I, Garrett MD.  CCT244747 is a novel potent and selective CHK1 inhibitor with oral efficacy alone and in combination with genotoxic anticancer drugs. Clin Cancer Res. 2012 Oct 15;18(20):5650-61.