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  2. Discovery of a small-molecule binder of the oncoprotein gankyrin that modulates gankyrin activity in the cell

Discovery of a small-molecule binder of the oncoprotein gankyrin that modulates gankyrin activity in the cell

  • Sci Rep. 2016 Apr 5;6:23732. doi: 10.1038/srep23732.
Anasuya Chattopadhyay 1 Cornelius J O'Connor 2 Fengzhi Zhang 2 Celine Galvagnion 2 Warren R J D Galloway 2 Yaw Sing Tan 2 3 Jamie E Stokes 2 Taufiq Rahman 1 Chandra Verma 3 4 5 David R Spring 2 Laura S Itzhaki 1
Affiliations

Affiliations

  • 1 Department of Pharmacology, Tennis Court Road, Cambridge CB2 1PD, UK.
  • 2 Department of Chemistry, Lensfield Road, Cambridge CB2 1EW, UK.
  • 3 Bioinformatics Institute (A*STAR), 30 Biopolis Street, #07-01 Matrix, Singapore 138671.
  • 4 School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
  • 5 Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543.
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.

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