title: Discovery of a small-molecule binder of the oncoprotein gankyrin that modulates gankyrin activity in the cell.
abstract: Gankyrin is an ankyrin-repeat oncoprotein whose overexpression has been implicated in the development of many cancer types. Elevated gankyrin levels are linked to aberrant cellular events including enhanced degradation of tumour suppressor protein p53, and inhibition of gankyrin activity has therefore been identified as an attractive anticancer strategy. Gankyrin interacts with several partner proteins, and a number of these protein-protein interactions (PPIs) are of relevance to cancer. Thus, molecules that bind the PPI interface of gankyrin and interrupt these interactions are of considerable interest. Herein, we report the discovery of a small molecule termed cjoc42 that is capable of binding to gankyrin. Cell-based experiments demonstrate that cjoc42 can inhibit gankyrin activity in a dose-dependent manner: cjoc42 prevents the decrease in p53 protein levels normally associated with high amounts of gankyrin, and it restores p53-dependent transcription and sensitivity to DNA damage. The results represent the first evidence that gankyrin is a "druggable" target with small molecules.
authors.affiliation: Department of Pharmacology, Tennis Court Road, Cambridge CB2 1PD, UK.
authors.forename: Anasuya
authors.initials: A
authors.lastname: Chattopadhyay
authors.affiliation: Department of Chemistry, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Cornelius J
authors.initials: CJ
authors.lastname: O'Connor
authors.affiliation: Department of Chemistry, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Fengzhi
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Celine
authors.initials: C
authors.lastname: Galvagnion
authors.affiliation: Department of Chemistry, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Warren R J D
authors.initials: WR
authors.lastname: Galloway
authors.affiliation: Department of Chemistry, Lensfield Road, Cambridge CB2 1EW, UK.|Bioinformatics Institute (A*STAR), 30 Biopolis Street, #07-01 Matrix, Singapore 138671.
authors.forename: Yaw Sing
authors.initials: YS
authors.lastname: Tan
authors.affiliation: Department of Chemistry, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Stokes
authors.affiliation: Department of Pharmacology, Tennis Court Road, Cambridge CB2 1PD, UK.
authors.forename: Taufiq
authors.initials: T
authors.lastname: Rahman
authors.affiliation: Bioinformatics Institute (A*STAR), 30 Biopolis Street, #07-01 Matrix, Singapore 138671.|School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.|Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543.
authors.forename: Chandra
authors.initials: C
authors.lastname: Verma
authors.affiliation: Department of Chemistry, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Spring
authors.affiliation: Department of Pharmacology, Tennis Court Road, Cambridge CB2 1PD, UK.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Itzhaki
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry; D064096:Aurora Kinase A / Q000378:metabolism; D001557:Benzenesulfonates / Q000737:chemistry*; D002151:Calorimetry; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D004249:DNA Damage; D004926:Escherichia coli / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051135:Rad51 Recombinase / Q000378:metabolism; D013816:Thermodynamics; D014230:Triazoles / Q000737:chemistry*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; C403591:PSMD10 protein, human; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; C122167:TPX2 protein, human; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; C000616231:cjoc42 compound; C576917:AURKA protein, human; D064096:Aurora Kinase A; D051135:Rad51 Recombinase; D046988:Proteasome Endopeptidase Complex