CCT-251921 is a potent, selective, and orally bioavailable CDK8 inhibitor with an IC50 of 2.3 nM.
CCT-251921 has acceptable aqueous solubility and demonstrates minimal activity when tested in a panel of 55 receptors, ion channels, and enzymes at 1 μM and in a panel of 279 kinases; weak inhibition of CYPs is observed. CCT-251921 demonstrates potent inhibition of reporter-based readouts measuring basal WNT pathway activity in human cancer cell lines that have constitutively activated WNT pathway signaling: LS174T (β-catenin mutant), SW480 and Colo205 (APC mutant) or PA-1 human teratocarcinoma cells that are WNT ligand dependent[1].
CCT-251921 shows improved oral pharmacokinetics and pharmaceutical properties in order to facilitate further evaluation of CDK8/19 pharmacology and progression into preclinical efficacy and safety studies. In APC-mutant SW620 human colorectal carcinoma xenograft model, CCT-251921 treatment reduces mice tumor weight (54.2%) at day 15. The inhibition of STAT1SER727 phosphorylation is maintained for more than 6 h after the last dose[1].
[1]. Mallinger A, et al. Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19. J Med Chem. 2016 Feb 11;59(3):1078-101.