2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19

摘要: We demonstrate a designed scaffold-hop approach to the discovery of 2,8-disubstituted-1,6-naphthyridine- and 4,6-disubstituted-isoquinoline-based dual CDK8/19 ligands. Optimized compounds in both series exhibited rapid aldehyde oxidase-mediated metabolism, which could be abrogated by introduction an amino substituent at C5 1,6-naphthyridine scaffold or C1 isoquinoline scaffold. Compounds 51 59 were progressed vivo pharmacokinetic studies, also demonstrated sustained inhibition STAT1(SER727) phosphorylation, biomarker CDK8 inhibition, SW620 colorectal carcinoma human tumor xenograft model following oral dosing.