2. Academic Validation
  3. Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19

Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19

  • J Med Chem. 2016 Feb 11;59(3):1078-101. doi: 10.1021/acs.jmedchem.5b01685.
Aurélie Mallinger 1,  Kai Schiemann 2,  Christian Rink 1,  Frank Stieber 2,  Michel Calderini 2,  Simon Crumpler 1,  Mark Stubbs 1,  Olajumoke Adeniji-Popoola 1,  Oliver Poeschke 2,  Michael Busch 2,  Paul Czodrowski 2,  Djordje Musil 2,  Daniel Schwarz 2,  Maria-Jesus Ortiz-Ruiz 1,  Richard Schneider 2,  Ching Thai 1,  Melanie Valenti 1,  Alexis de Haven Brandon 1,  Rosemary Burke 1,  Paul Workman 1,  Trevor Dale 3,  Dirk Wienke 2,  Paul A Clarke 1,  Christina Esdar 2,  Florence I Raynaud 1,  Suzanne A Eccles 1,  Felix Rohdich 2,  Julian Blagg 1
Affiliations

Affiliations

  • 1 Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K.
  • 2 Merck KGaA , Darmstadt, 64293, Germany.
  • 3 School of Bioscience, Cardiff University , Cardiff, CF10 3AX, U.K.
PMID: 26796641 DOI: 10.1021/acs.jmedchem.5b01685
Abstract

The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal Cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of Cancer.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-19984
    98.86%, CDK 抑制剂
    CDK
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