Developing inhibitors to target activated fibroblasts
A drug discovery program has led to promising and selective pharmacological inhibitors of PNK2 to target activated fibroblasts in cancer and other fibrotic diseases.
Deletion of PKN2 can suppress the differentiation of fibroblasts into myofibroblasts; the established source of cancer-associated fibroblasts in tumours. A number of pro-tumourigenic functions of fibroblasts are suppressed by loss of this protein kinase, including growth and invasion in breast and pancreatic cancer models. Additionally, PKN2 has been identified as a co-dependent kinase for YAP, essential for cancer initiation or growth of most solid tumors.
Selective pharmacological inhibitors do not however exist. Identified inhibitors will have commercial potential for treatment of fibrotic cancers, fibrotic disease and in academia.
In collaboration with the Dundee Drug Discovery Unit (DDU), we have screened compound libraries for tool compounds against PKN2. Studies have identified validated candidate inhibitors showing dose dependent activity and these hits have been revalidated and expanded through repurchasing compounds and conducting cluster expansion studies. Lead compounds show high selectivity for the target and have highly favourable chemical characteristics for use in cell models.
Future work aims to optimise potency for in vitro use and develop leads into inhibitors suitable for in vivo pre-clinical studies and to progress crystallography studies. In addition to the drug discovery pipeline, there is ongoing work to generate pharmacokinetic biomarkers for testing compound efficacy in cells and ultimately in vivo. A panel of candidate direct substrates have been identified using a combination of mass-spectrometry, kinase substrate specificity and in vitro assays.
We are now seeking partners or investment to further develop these lead compounds.
Dr Mark Gurden – email@example.com