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A Dual Non-ATP Analogue Inhibitor of Aurora Kinases A and B, Derived from Resorcinol with a Mixed Mode of Inhibition
Aurora kinases are the most commonly targeted mitotic kinases in the intervention of cancer progression. Here, we report a resorcinol derivative, 5‐methyl‐4‐(2‐thiazolylazo) resorcinol (PTK66), a dual inhibitor of Aurora A and Aurora B kinases. PTK66 is a surface binding non‐ATP analogue inhibitor t...
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Published in: | Chemical biology & drug design 2016-06, Vol.87 (6), p.958-967 |
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Main Authors: | , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Aurora kinases are the most commonly targeted mitotic kinases in the intervention of cancer progression. Here, we report a resorcinol derivative, 5‐methyl‐4‐(2‐thiazolylazo) resorcinol (PTK66), a dual inhibitor of Aurora A and Aurora B kinases. PTK66 is a surface binding non‐ATP analogue inhibitor that shows a mixed pattern of inhibition against both of Aurora A and B kinases. The in vitro IC50 is approximately 47 and 40 μm for Aurora A and Aurora B kinases, respectively. In cellular systems, PTK66 exhibits a substantially low cytotoxicity at micromolar concentrations but it can induce aneuploidy under similar dosages as a consequence of Aurora kinase inhibition. This result was corroborated by a drop in the histone H3 (S10) phosphorylation level detected via Western blot analysis using three different cell types. Altogether, our findings indicate that the ligand containing resorcinol backbone is one of the novel scaffolds targeting the Aurora family of kinases, which could be a target for antineoplastic drug development.
PTK66, a non‐ATP analogue inhibitor of Aurora kinases A and B, disrupts the function of these kinases to create mitotic defects. PTK66 exhibits a substantially low cytotoxicity at micromolar concentrations but it can induce aneuploidy under similar dosages as a consequence of Aurora kinase inhibition. Altogether, our findings indicate that this ligand, containing resorcinol backbone, is one of the novel scaffolds targeting the Aurora family of kinases, which could be a target for antineoplastic drug development. |
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ISSN: | 1747-0277 1747-0285 |
DOI: | 10.1111/cbdd.12728 |