title: A Casein kinase 1/Checkpoint kinase 1 pyrazolo-pyridine protein kinase inhibitor as novel activator of the p53 pathway.
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.
authors.affiliation: 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.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Huart
authors.forename: Barbara
authors.initials: B
authors.lastname: Saxty
authors.forename: Andy
authors.initials: A
authors.lastname: Merritt
authors.forename: Marta
authors.initials: M
authors.lastname: Nekulova
authors.forename: Stephen
authors.initials: S
authors.lastname: Lewis
authors.forename: Yide
authors.initials: Y
authors.lastname: Huang
authors.forename: Borivoj
authors.initials: B
authors.lastname: Vojtesek
authors.forename: Catherine
authors.initials: C
authors.lastname: Kettleborough
authors.forename: Ted R
authors.initials: TR
authors.lastname: Hupp
mesh_terms: D047389:Casein Kinase I / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D045325:HCT116 Cells; D006801:Humans; D007700:Kinetics; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000819:agonists* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C118531:pyrazolopyridine; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D047389:Casein Kinase I; D000071877:Checkpoint Kinase 1
keywords: Casein kinase 1; Checkpoint kinase 1; Kinase inhibitor; p53 Pathway activation