Benefits
- Analysis of multiple drug classes for kinase inhibition
- Enables interpretation of potential toxicity-MOA and selection of superior candidate compounds
- Guides understanding of potential off-target liabilities with broad selectivity information
- Build knowledgebase with selectivity, potency, toxicity SAR
Leveraging Kinome-wide Profiling to Reveal Off-Target Interactions
More than half of discovery compounds undergo safety-related attrition. Kinome-wide profiling has emerged as an important strategy for identifying potential compound off-target liabilities, while broad selectivity information supports the identification and development of high quality starting points with the best probability of clinical success.
Given the highly conserved catalytic domains between kinases, and the general affinity for ATP, selectively targeting the ATP-site of a kinase with small molecule inhibitors, once viewed by many scientists as difficult or impossible, has since yielded multiple FDA approved small molecule kinase inhibitors with over 500 more in active development. While kinase inhibitors demonstrate great promise for disease treatment and management, compound selectivity remains a common challenge in drug development.
The tendency of small molecules to interact with multiple kinases presents both an opportunity and challenge for drug discovery: Inhibiting the therapeutic targets alone reduces the potential for unwanted off-target effects and associated toxicities.Conversely, some off-target kinases may be important therapeutic targets in other diseases. Hence, selectivity is an important consideration for development of compounds in this target class and kinome-wide profiling has emerged as an important strategy in compound safety.
KINOME
scan affords an unprecedented view of global selectivity with the largest commercial panel of kinase assays and can identify unanticipated off-target binding, which can be missed using smaller assay panels. Combined with additional pharmacological and toxicological data, kinome-wide annotation provides important information about potential off-target liabilities to better inform compound safety and reduce attrition. Selectivity data is key to support selection of superior candidates with the best chance for success.
Services & Solutions
The largest commercial kinase panel available,
scanMAX contains a definitive set of 451 kinases covering AGC, CAMK, CMGC, CK1, STE, TK, TKL, lipid and atypical kinase families, plus important mutant forms.
Quantitate compound binding affinity against any KINOME
scan kinase assay. Inhibitor binding constants (Kd values) are calculated from duplicate 11-point dose-response curves (plus DMSO control). Measurements are made under optimized conditions that generate true thermodynamic Kd values.
Complete Kd profile of the
scanMAX panel. Recommended for candidate compounds
Effect of Panel Size on Selectivity Profile
Panel Size Matters: Small Assay Panels Do not
Provide a Robust Measure of Selectivity
For each compound selectivity scores were calculated for panels ranging in size from 20 to 288 assays, randomly chosen (500 random panels of each size) [click to enlarge].
JAK Inhibitor TG-101348
Selectivity of JAK inhibitor TG-101348 was reported in published findings to be a selective pan-JAK inhibitor on the basis of kinase profiling against a panel of 37 kinases. In contrast, selectivity profiling against the scanMAX kinase assay panel (then 402) revealed additional interactions not previously identified [click graph to enlarge].
RSK Inhibitor BI-D1870
Selectivity of RSK inhibitor BI-D1870 was reported in published findings to be a selective RSK kinase inhibitor on the basis of kinase profiling against a panel of 54 kinases. In contrast, selectivity profiling against the scanMAX kinase assay panel (then 402) revealed additional interactions not previously identified [click graph to enlarge].