WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. CDK8 as part of the Mediator complex has been reported to regulate basal transcription by phosphorylation of RNA polymerase II and to phosphorylate E2F1 thereby activating WNT signaling. CDK8 gene expression also correlates with increased mortality in colorectal, breast and ovarian cancers and is also overexpressed and essential for cell proliferation in melanoma. Therefore it plays an important role in oncogenesis. Here we report the discovery and optimization of a 3-benzylindazole series - originally developed as HSP90 inhibitors - identified from an HTS screen on CDK8/cyclin C with activity in a cell-based reporter assay of the WNT pathway. We disclose X-ray co-crystal structures and medicinal chemistry optimization to increase potency, improve physicochemical properties and oral pharmacokinetics. In addition, the kinase selectivity and off-target profiles will be shown and <i>in vivo</i> biomarker activity after oral dosing demonstrated.

CDK8/19 inhibitors: 3-benzylindazoles

251st National Meeting (2016)

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