American Chemical Society
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 McInnes
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.