Structural highlights
Publication Abstract from PubMedThe atypical protein kinase C (aPKC) isoforms iota (iota) and zeta (zeta) 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. Here 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 PKCiota 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 lethal giant larvae 2 (LLGL2) phosphorylation in cell lines and exhibits phenotypic effects in a range of cell-based assays. We conclude that this compound has utility as a chemical tool to modulate aPKC activity in vitro and in vivo and may guide the search for further aPKC-selective inhibitors. Adenosine-binding motif mimicry and cellular effects of a thieno[2,3-d]pyrimidine-based chemical inhibitor of atypical protein kinase C isozymes.,Kjaer S, Linch M, Purkiss A, Kostelecky B, Knowles PP, Rosse C, Riou P, Soudy C, Kaye S, Patel B, Soriano E, Murray-Rust J, Barton C, Dillon C, Roffey J, Parker PJ, McDonald NQ Biochem J. 2013 Feb 18. PMID:23418854[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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