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A Casein kinase 1/Checkpoint kinase 1 pyrazolo-pyridine protein kinase inhibitor as novel activator of the p53 pathway |
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| Authors: | Anne-Sophie Huart Barbara Saxty Andy Merritt Marta Nekulova Stephen Lewis Yide Huang Borivoj Vojtesek Catherine Kettleborough Ted R. Hupp |
| Affiliation: | 1. p53 Signal Transduction Group, University of Edinburgh Cancer Research Centre in the Institute of Genetics and Molecular Medicine, Crewe Road South, Edinburgh EH4 2XR, United Kingdom;2. Medical Research Council Technology, Mill Hill, London NW7 1AD, United Kingdom;3. Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno 656 53, Czech Republic;4. College of Life Sciences, Fujian Normal University, Fuzhou, Fujian 350108, People’s Republic of China |
| Abstract: | Reactivation of the wild-type p53 pathway is one key goal aimed at developing targeted therapeutics in the cancer research field. Although most p53 protein kinases form ‘p53-activating’ signals, there are few kinases whose action can contribute to the inhibition of p53, as Casein kinase 1 (CK1) and Checkpoint kinase 1 (CHK1). Here we report on a pyrazolo-pyridine analogue showing activity against both CK1 and CHK1 kinases that lead to p53 pathway stabilisation, thus having pharmacological similarities to the p53-activator Nutlin-3. These data demonstrate the emerging potential utility of multivalent kinase inhibitors. |
| Keywords: | Kinase inhibitor p53 Pathway activation Casein kinase 1 Checkpoint kinase 1 |
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