Abstract C95: A flexible kinase inhibitor assay platform for active, nonactivated, and impure kinase preparations.

Abstract

Kinase activity-based assays are cost-effective and widely used to drive early drug discovery and lead identification, however, they typically require purified, active kinase preparations be produced that are shown to phosphorylate a known substrate. While it is possible to satisfy these requirements for the well-studied kinases, there are many kinases which lack one or more of these requirements, such as CDK8 and STK33, making drug discovery efforts difficult. To solve for these assay development problems, we have developed a TR-FRET-based binding assay platform which allows for characterization of compounds with kinases that are not sufficiently purified or do not demonstrate measurable activity against putative or potential substrates. This assay addresses kinase assay requirements early in the drug discovery process, and should enable more targets to be screened sooner, resulting in compounds being made available for lead optimization faster. The ability to detect and characterize binding of compounds to non-activated kinases is also a benefit to the lead optimization process, as compounds that bind preferentially to kinases in their non-activated state, such as Imatinib, are sometimes preferred due to their selectivity. In this poster, we present solutions for kinases that are difficult to address with activity assays and provide a comparison of compound affinities for active and non-activated forms of a diverse set of kinases to enable faster lead optimization. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C95.