CCT251545 analogue, Compound 51 is a potent and selective CDK8/19 inhibitor with IC50 values of 5.1 nM and 5.6 nM, respectively [1].
Mediator complex-associated kinases CDK8 and CDK19 are involved in the regulation of multiple transcription pathways. CDK8 plays as an oncogene in gastric and colorectal cancers through activation of WNT signaling [1].
CCT251545 analogue, Compound 51 is a potent and selective CDK8/19 inhibitor. In SW620 human colorectal carcinoma cells harbouring activating APC-mutation, Compound 51 inhibited phospho-STAT1SER727 with IC50 value of 17.9 nM, a biomarker of CDK8 inhibition [1].
In vivo mouse and rat PK experiments, Compound 51 demonstrated medium in vivo clearance and Vd but low bioavailability in mice. In a SW620 colorectal carcinoma human tumor xenograft model, Compound 51 (5 mg/kg po dose) inhibited phospho-STAT1SER727 in a time-dependent way. Compound 51 is an advanced chemical tool to further explore the efficacy, safety and tolerability of dual CDK8/19 ligands [1].
Reference:
[1].Mallinger A, Schiemann K, Rink C, et al. 2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19. ACS Med Chem Lett. 2016 Mar 28;7(6):573-8.