A Selective and Orally Bioavailable Quinoline-6-Carbonitrile-Based Inhibitor of CDK8/19 Mediator Kinase with Tumor-Enriched Pharmacokinetics
- Li ZhangLi ZhangDepartment of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United StatesMore by Li Zhang
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- Chen ChengChen ChengDepartment of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United StatesMore by Chen Cheng
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- Jing LiJing LiDepartment of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United StatesMore by Jing Li
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- Lili WangLili WangDepartment of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United StatesMore by Lili Wang
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- Alexander A. ChumanevichAlexander A. ChumanevichDepartment of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United StatesMore by Alexander A. Chumanevich
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- Donald C. PorterDonald C. PorterSenex Biotechnology, Inc., Columbia, South Carolina 29208, United StatesMore by Donald C. Porter
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- Aleksei MindichAleksei MindichCSC BIOCAD, Strelna, Saint-Petersburg 198515, RussiaBiotechnology Department, Sirius University of Science and Technology, Sochi 354340, RussiaMore by Aleksei Mindich
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- Svetlana Gorbunova
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- Igor B. RoninsonIgor B. RoninsonDepartment of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United StatesSenex Biotechnology, Inc., Columbia, South Carolina 29208, United StatesMore by Igor B. Roninson
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- Mengqian Chen*Mengqian Chen*Email: [email protected]Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United StatesSenex Biotechnology, Inc., Columbia, South Carolina 29208, United StatesMore by Mengqian Chen
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- Campbell McInnes*Campbell McInnes*Email: [email protected]Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United StatesMore by Campbell McInnes
Abstract
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.
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