Abstract 2322: Primary structure-promiscuity relationships (PSPRs) of tyrosine kinases
Authors: Shallal Hassan M. , Russu Wade A. 
Published: June 2012

Introduction: Whether they are type-I or type-II, it is reported that the majority of kinase inhibitors, except for lapatinib, are non-selective kinase binders. This prompted us to ask the following question: are there any relationships between the primary amino acid sequence of kinases and their potential to bind to a structurally diverse group of kinase inhibitors? This general question can be further broken down into three more specific questions. Close to and within the ATP-binding site, what are the points that are non-conserved among a set of several kinases? In a given non-conserved point, are there certain amino acids that favor the overall promiscuity of certain kinases over others? Considering a specific non-conserved point, how can different amino acids affect the binding potential of a given kinase inhibitor to different kinases? Datasets and Methods: we used a reported dataset that describes the binding of a group of 38 structurally diverse kinase inhibitors against 77 wild-type tyrosine kinases using a commercial binding screen (KinomeScanTM). The binding was described as yes for an inhibitor binding to a kinase with a Kd ≤ 10 µM and no for an inhibitor binding to a kinase with a Kd &gt; 10 µM. Sequence alignment, using ClustalX 1.83, of the 77 tyrosine kinases helped reveal a group of 15 non-conserved points within the primary amino acid sequence that can act as candidates of promiscuity markers. Both Kruskal Wallis one way analysis of variance by ranks, a non-parametric based statistical analysis, and Dunn's post-hoc statistical testing with a significance level of 95% confidence interval were used to statistically test the relationship between the amino acid variation within each non-conserved point and the promiscuity of the 77 tyrosine kinases towards the 38 kinase inhibitors. Results: different amino acid residues within 9 out of the 15 tested non-conserved points were found to be statistically relevant to the promiscuity of tyrosine kinases. Considering the gatekeeper position as an example, either threonine or valine residue were found to be common among more promiscuous tyrosine kinases compared to methionine common among less promiscuous tyrosine kinases. This could be either an individual influence by the gatekeeper residue or a combined effect of it along with other residues. Furthermore, certain amino acids at a given point were found to favor the binding of a given kinase inhibitor to kinases having these amino acids in that specific point and vice versa. For instance, methionine, as a gatekeeper residue of several tyrosine kinases, was statistically correlated with the inability of these kinases to bind to dasatinib, sorafenib, imatinib and many other kinase inhibitors. Interestingly enough, certain selectivity markers were found to be statistically significant to the selective binding of lapatinib against EGFR subfamily members. This poster will describe the obtained results and discuss their significance.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2322. doi:10.1158/1538-7445.AM2011-2322