| Autor: |
KJÆR, Svend, LINCH, Mark, PURKISS, Andrew, KOSTELECKY, Brenda, KNOWLES, Phillip P., ROSSE, Carine, RIOU, Philippe, SOUDY, Christelle, KAYE, Sarah, PATEL, Bhavisha, SORIANO, Erika, MURRAY-RUST, Judith, BARTON, Caroline, DILLON, Christian, ROFFEY, Jon, PARKER, Peter J., MCDONALD, Neil Q. |
| Předmět: |
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| Zdroj: |
Biochemical Journal; 4/15/2013, Vol. 451 Issue 2, p329-342, 17p |
| Abstrakt: |
The aPKC [atypical PKC (protein kinase C)] isoforms i 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 PKCé 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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