jm1c01951_si_004.pdb (647.9 kB)
A Selective and Orally Bioavailable Quinoline-6-Carbonitrile-Based Inhibitor of CDK8/19 Mediator Kinase with Tumor-Enriched Pharmacokinetics
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posted on 2022-02-03, 23:13 authored by Li Zhang, Chen Cheng, Jing Li, Lili Wang, Alexander A. Chumanevich, Donald C. Porter, Aleksei Mindich, Svetlana Gorbunova, Igor B. Roninson, Mengqian Chen, Campbell McInnesSenexins
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.
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enriched pharmacokinetics senexins11 leukemia growth19 mediator kinases19 mediator kinase19 inhibitory activityguided strategy basedselective quinazoline inhibitorspd marker responsesorally bioavailable quinolineenrichment pk profile20a bexhibits potent cdk8based inhibitorbased derivativesvivo pharmacokineticvivo modelsustained inhibitionsar ).optimized compoundmetabolically stablemetabolic stabilityhigh selectivitygood tolerabilityevaluation using