Comparative analysis of the human and zebrafish kinomes: focus on the development of kinase inhibitors.

Targeting kinases with semi-selective kinase inhibitors is one of the most successful drug development strategies of the 21^st century. Zebrafish have become an increasingly useful model for pharmaceutical development. Water-soluble compounds can be screened for zebrafish phenotypes in a high throughput format against a living vertebrate, and cell-signaling events can be imaged in transparent living fish. Despite zebrafish being a more relevant model than more distantly related systems such as the well-annotated kinome of yeast and drosophila, there is no comparative analysis of the human and zebrafish kinome. Furthermore most approved kinase inhibitors, often called 'DFG in' ATP competitive inhibitors, act on conserved active site residues in the kinase. Since the active site residues can be identified by examining the primary sequence, primary sequence identity can be a rough guide as to whether a particular inhibitor will have activity against another kinase. There is a need to evaluate the utility of zebrafish as a drug development model for active site inhibitors of kinases. Here we offer a systematic comparison of the catalytic domains of classical human kinases with the catalytic domains of all annotated zebrafish kinases. We found a high degree of identity between the catalytic domains of most human kinases and their zebrafish homologs, and we ranked 504 human kinase catalytic domains by order of similarity. We found only 23 human kinases with no easily recognizable homologous zebrafish catalytic domain. On the other hand we found 78 zebrafish kinase catalytic domains with no close human counterpart. These 'additional kinase active sites' could represent potential mediators of zebrafish toxicity that may not be relevant to human kinase inhibitors. We used two clinically approved human kinase inhibitors, one targeting a highly homologous target and one targeting a lesser homologous target, and we compared the known human kinase target structures with modeled zebrafish target structures. As expected, the homologous target had high structural identity, but even the less homologous target had high structural identity in residues contacted by the inhibitor. Overall this analysis should help guide researchers interested in studying human kinases and their inhibitors in more tractable systems.

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