Article Metrics


Online attention

Adenosine-Binding Motif Mimicry and Cellular Effects of a Thieno[2,3-D]Pyrimidine-Based Chemical Inhibitor of Atypical Protein Kinase C Isozymes

DOI: 10.1042/BJ20121871 DOI Help
PMID: 23418854 PMID Help

Authors: Svend Kjær (Cancer Research UK) , Mark Linch (Cancer Research UK) , Andy Purkiss (Cancer Research UK London Research Institute) , Brenda Kostelecky (Cancer Research UK London Research Institute) , Phillip Knowles (Cancer Research UK London Research Institute) , Carine Rosse (Cancer Research UK) , Philippe Riou (Cancer Research UK) , Christelle Soudy (University College London) , Sarah Kaye (University College London) , Bhavisha Patel (University College London) , Erika Soriano (Cancer Research UK London Research Institute) , Judith Murray‑rust (Cancer Research UK) , Caroline Barton (University College London) , Christian Dillon (University College London) , Jon Roffey (University College London) , Peter j. Parker (Cancer Research UK) , Neil Mcdonald (Cancer Research UK London Research Institute)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochemical Journal , VOL 451 , PAGES 329 - 342

State: Published (Approved)
Published: April 2013
Diamond Proposal Number(s): 8015

Abstract: The aPKC [atypical PKC (protein kinase C)] isoforms ι and ζ play crucial roles in the formation and maintenance of cell polarity and represent attractive anti-oncogenic drug targets in Ras-dependent tumours. To date, few isoform-specific chemical biology tools are available to inhibit aPKC catalytic activity. In the present paper, we describe the identification and functional characterization of potent and selective thieno[2,3-d]pyrimidine-based chemical inhibitors of aPKCs. A crystal structure of human PKCι kinase domain bound to a representative compound, CRT0066854, reveals the basis for potent and selective chemical inhibition. Furthermore, CRT0066854 displaces a crucial Asn-Phe-Asp motif that is part of the adenosine-binding pocket and engages an acidic patch used by arginine-rich PKC substrates. We show that CRT0066854 inhibits the LLGL2 (lethal giant larvae 2) phosphorylation in cell lines and exhibits phenotypic effects in a range of cell-based assays. We conclude that this compound can be used as a chemical tool to modulate aPKC activity in vitro and in vivo and may guide the search for further aPKC-selective inhibitors.

Journal Keywords: Adenosine; Amino; Animals; Binding; Cell;Cell; Crystallography; X-Ray; Cytoskeletal; Dogs; Drug; Preclinical; High-Throughput; Humans; Inhibitory; Isoenzymes;Phosphorylation; Protein; Pyrimidines; Thiophenes

Subject Areas: Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography