2. Academic Validation
  3. Discovery of potent and selective CDK8 inhibitors from an HSP90 pharmacophore

Discovery of potent and selective CDK8 inhibitors from an HSP90 pharmacophore

  • Bioorg Med Chem Lett. 2016 Mar 1;26(5):1443-51. doi: 10.1016/j.bmcl.2016.01.062.
Kai Schiemann 1,  Aurélie Mallinger 2,  Dirk Wienke 3,  Christina Esdar 3,  Oliver Poeschke 3,  Michael Busch 3,  Felix Rohdich 3,  Suzanne A Eccles 2,  Richard Schneider 3,  Florence I Raynaud 2,  Paul Czodrowski 3,  Djordje Musil 3,  Daniel Schwarz 3,  Klaus Urbahns 3,  Julian Blagg 2
Affiliations

Affiliations

  • 1 Merck KGaA, 64293 Darmstadt, Germany. Electronic address: [email protected].
  • 2 Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London SW7 3RP, UK.
  • 3 Merck KGaA, 64293 Darmstadt, Germany.
PMID: 26852363 DOI: 10.1016/j.bmcl.2016.01.062
Abstract

Here we describe the discovery and optimization of 3-benzylindazoles as potent and selective inhibitors of CDK8, also modulating CDK19, discovered from a high-throughput screening (HTS) campaign sampling the Merck compound collection. The primary hits with strong HSP90 affinity were subsequently optimized to potent and selective CDK8 inhibitors which demonstrate inhibition of Wnt pathway activity in cell-based assays. X-ray crystallographic data demonstrated that 3-benzylindazoles occupy the ATP binding site of CDK8 and adopt a Type I binding mode. Medicinal chemistry optimization successfully led to improved potency, physicochemical properties and oral pharmacokinetics. Modulation of phospho-STAT1, a pharmacodynamic biomarker of CDK8, was demonstrated in an APC-mutant SW620 human colorectal carcinoma xenograft model following oral administration.

Keywords

CDK19; CDK8; HSP90; Indazoles; Mediator complex; WNT pathway inhibitors.

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