Approximately 518 kinases are encoded by the human genome and serve as critical mediators of signal transduction brought about by a phosphorylation event. Many kinases are known to be involved in diabetes, inflammation, cardiovascular diseases, tumor cell proliferation and metastasis and are therefore validated targets for therapeutic intervention. Currently there are 10 marketed kinase drugs, another 80 inhibitors are in clinical trials and many more are being evaluated in the preclinical stage. The kinases share a relatively similar architecture at the active-site (ATP-binding domain), making selectivity an issue in drug discovery and development. A promiscuous or 'dirty'drug, which binds to many kinases, is expected to give rise to unwanted adverse-effects. At the same time, in some cases, inhibiting multiple targets, like kinases, selectively in a signal transduction pathway might be a desired strategy for treating a disease. Profiling drug candidates against a large panel of kinases can therefore not only aid in anticipating toxicity profiles, but also help in identifying new targets for old compounds. In this Phase II application, we will develop our split-luciferase based luminescent assays for kinome-wide profiling. Currently due to the high costs of profiling against kinases, selectivity profiles are typically obtained later in drug development to verify the lead compound's specificity. In addition, many researchers are shut out on a routine basis. Our goal is to make these profiling assays affordable, so that compound profiling can be done earlier leading to early identification of failures and resulting in many more opportunities for success.
Kinases are important mediators of signal transduction pathways and their activity inside cells is tightly regulated. Dysregulation of kinases has been implicated in many diseases, validating them as therapeutic targets. The challenge in designing drugs against kinases comes from their cross-reactivity, which arises due to similar architecture of many kinases at the ATP-binding site. Screening compounds against a large number of kinases can help develop a selectivity fingerprint, which can be used to make important decisions for advancing a compound into the clinic. The purpose of our application is to develop low-cost, sensitive, luminescence based kinase assays for drug discovery.
|Jester, Benjamin W; Gaj, Alicia; Shomin, Carolyn D et al. (2012) Testing the promiscuity of commercial kinase inhibitors against the AGC kinase group using a split-luciferase screen. J Med Chem 55:1526-37|