A quantitative analysis of kinase inhibitor selectivity

Abstract

Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

“…Interestingly, in primary cell lysates, c-midostaurin recognized BTK (Supplementary Table S2, Figure 4B). Most of these kinase targets were also identified by midostaurin in a cellfree system (29). In control experiments, we were able to show that midostaurin and cmidostaurin inhibit growth of HMC-1.…”

“…However, midostaurin also interacts with other target-antigens, such as PDGFR, FLT3 and PKC (27,29). We asked whether the target-spectrum of CGP52421 differs from that of midostaurin.…”

“…PKC412 (midostaurin) is a multi-kinase inhibitor directed against wild type (wt) KIT and several KIT mutants, including D816V (21,27,28). Additional oncogenic kinases are also recognized by midostaurin (27,29). However, the exact profile of molecular targets of midostaurin expressed by neoplastic MC remains unknown.…”

Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double‐blind, methotrexate‐controlled study of patients with active rheumatoid arthritis

“…While the results of this study are disappointing, over time the p38 inhibitors have become progressively more potent and selective (27). In addition, studies are ongoing in neuropathic pain, chronic obstructive pulmonary disease, atherosclerosis, and oncologic indications as well as in RA (28).…”

Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib

“…A recent study that examined the activity of sunitinib against a panel of 317 kinases (representing 450% of the known kinome) revealed that sunitinib has relatively high affinity for at least 40 other kinases, including myosin light-chain kinase, MEK1 and MEK2 (Karaman et al, 2008). As activation of multiple kinase-signalling pathways is a requirement for growth factor-mediated stimulation of angiogenesis, the relatively broad kinase substrate specificity of sunitinib might be expected to limit the potential for other growth factors to drive resistance to sunitinib through a mechanism that involves direct stimulation of endothelial cells.…”