A Selective and Orally Bioavailable Quinoline-6-Carbonitrile-Based Inhibitor of CDK8/19 Mediator Kinase with Tumor-Enriched Pharmacokinetics

Senexins
are potent and selective quinazoline inhibitors of CDK8/19
Mediator kinases. To improve their potency and metabolic stability,
quinoline-based derivatives were designed through a structure-guided
strategy based on the simulated drug–target docking model of
Senexin A and Senexin B. A library of quinoline-Senexin derivatives was synthesized to explore the
structure–activity relationship (SAR). An optimized compound 20a (Senexin C) exhibits potent CDK8/19 inhibitory activity
with high selectivity. Senexin C is more metabolically stable and
provides a more sustained inhibition of CDK8/19-dependent cellular
gene expression when compared with the prototype inhibitor Senexin
B. In vivo pharmacokinetic (PK) and pharmacodynamic (PD) evaluation
using a novel tumor-based PD assay showed good oral bioavailability
of Senexin C with a strong tumor-enrichment PK profile and tumor-PD
marker responses. Senexin C inhibits MV4-11 leukemia growth in a systemic
in vivo model with good tolerability.