A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery

Abstract

Despite the development of a number of efficacious kinase inhibitors, the strategies for rational design of these compounds have been limited by target promiscuity. In an effort to better understand the nature of kinase inhibition across the kinome, especially as it relates to off-target effects, we screened a well-defined collection of kinase inhibitors using biochemical assays for inhibitory activity against 234 active human kinases and kinase complexes, representing all branches of the kinome tree. For our study we employed 158 small molecules initially identified in the literature as potent and specific inhibitors of kinases important as therapeutic targets and/or signal transduction regulators. Hierarchical clustering of these benchmark kinase inhibitors on the basis of their kinome activity profiles illustrates how they relate to chemical structure similarities and provides new insights into inhibitor specificity and potential applications for probing new targets. Using this broad dataset, we provide a framework for assessing polypharmacology. We not only discover likely off-target inhibitor activities and recommend specific inhibitors for existing targets, but also identify potential new uses for known small molecules.

Indole-like Trk receptor antagonists

“…However, a recent extensive analysis of kinase inhibitors, which also addressed some Syk inhibitors, including the compound named here as 2a21, concluded that three of the tested "Syk inhibitors" had extremely different selectivity among a wide range of kinases and only one of these three compounds was a potent Syk inhibitor [57]. It is noteworthy that our results highly correlate with the results of this study e at 1 mM concentration of 2a21 Gao et al…”

JNK2 controls fragmentation of the Golgi complex and the G2/M transition through phosphorylation of GRASP65

“…To confirm this finding using an independent approach we used two additional structurally unrelated JNK inhibitors (JNK inhibitors VIII and III; Gao et al, 2013) to monitor GRASP65-Ser277 phosphorylation in NRK cells. These cells were arrested in S phase using an aphidicolin block.…”

An In Vivo Functional Screen Identifies JNK Signaling As a Modulator of Chemotherapeutic Response in Breast Cancer

“…To confirm that the effect of JNK downregulation was due to loss of JNK catalytic activity, 4T1-Luc cells were treated with increasing concentrations of three chemically distinct pan-JNK small-molecule inhibitors, SP600125 (28), JNK inhibitor VIII (29,30), and JNK-IN-8 (13). JNK inhibition was monitored by a decrease in Ser63 phosphorylation of the JNK downstream target c-Jun (Fig.…”