CCT244747 is a potent inhibitor of checkpoint kinase 1 (Chk1; IC50 = 8 nM). It is selective for Chk1 over FLT3, Chk2, and CDK1 (IC50s = 600, >10,000, and >10,000 nM, respectively) as well as a panel of 121 additional kinases at a concentration of 10 μM. CCT244747 reverses cell cycle arrest at the G2/M phase induced by etoposide and SN-38 in HT-29 cells and gemcitabine (Item Nos. 11690 | 9003096) in SW620 cells, indicating cellular G2 checkpoint abrogation. It potentiates the genotoxicity of SN-38, gemcitabine, and etoposide in HT-29, SW620, MiaPaCa-2, and Calu-6 cells with potentiation index (PI) values ranging from 1.9-8.5, 2.6-12.2, 5-16, and 1.4-5.6, respectively. In vivo, CCT244747 (75 mg/kg), in combination with irinotecan or gemcitabine, increases the delay of tumor growth in SW620 and Calu-6 mouse xenograft models, respectively.
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].
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].
[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.
