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Factors influencing the inhibition of protein kinases

Brockhoff, Marielle, Hau, Jean-Christophe, Fontana, Patrizia, Zimmermann, Catherine, De Pover, Alain, Erdmann, Dirk and Chene, Patrick (2012) Factors influencing the inhibition of protein kinases. Journal of Enzyme Inhibition and Medicinal Chemistry, 27 (2). pp. 194-200. ISSN 1475-6366


The protein kinase field is a very active research area in the pharmaceutical industry and many activities are ongoing to identify inhibitors of these proteins. The design of new chemical entities with improved pharmacological properties requires a deeper understanding of the factors that modulate inhibitor-kinase interactions. In this report, we study the effect of two of these factors – the magnesium ion cofactor and the protein substrate – on inhibitors of the type I insulin-like growth factor receptor. Our results show that the concentration of magnesium ion influences the potency of ATP competitive inhibitors, suggesting an explanation for the observation that such compounds retain their nanomolar potency in cells despite the presence of millimolar levels of ATP. We also show that the peptidic substrate affects the potency of these IGF1R ATP competitive inhibitors in a different manner, suggesting that the influence of this substrate on compound potency should be taken into consideration during compound optimization.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Restrictions: 12 month embargo for STM, Behavioural Science and Public Health Journals 18 month embargo for SSH journals
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15


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