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

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

  • J Med Chem. 2022 Feb 24;65(4):3420-3433. doi: 10.1021/acs.jmedchem.1c01951.
Li Zhang 1 Chen Cheng 1 Jing Li 1 Lili Wang 1 Alexander A Chumanevich 1 Donald C Porter 2 Aleksei Mindich 3 4 Svetlana Gorbunova 3 Igor B Roninson 1 2 Mengqian Chen 1 2 Campbell McInnes 1
Affiliations

Affiliations

  • 1 Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United States.
  • 2 Senex Biotechnology, Inc., Columbia, South Carolina 29208, United States.
  • 3 CSC BIOCAD, Strelna, Saint-Petersburg 198515, Russia.
  • 4 Biotechnology Department, Sirius University of Science and Technology, Sochi 354340, Russia.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-143889
    98.82%, CDK8/19抑制剂
    CDK