Products & Applications / Toxicity & Safety

Compound Safety & Liability Screening

Reveal Off-Target Interactions with Kinome- & GPCRome-Wide Profiling

Target profiling and lead optimization are critical stages for all drug discovery programs. Compounds are tested against a broad range of kinase and/or GPCR targets to determine levels of inhibition, activation, and potential off-target liabilities of the target of interest. Assessing the specificity of lead compounds early in development using highly relevant and predictive panels allows more informed decisions about compound safety, ultimately leading to the development of safer and more effective drugs.

Non-specific cross reactivity for both kinases and GPCR targets can lead to dangerous side-effects and other liabilities. Given the highly conserved catalytic domains between kinases and the general affinity for ATP, selective targeting of the ATP-site of a kinase by small-molecule inhibitors remains a common challenge in kinase drug development. In addition, many of the approximately 385 “druggable” GPCRs (excluding taste and odorant receptors) share a similar small-molecule binding pocket, which means that one drug often interacts with many different receptors.

DiscoveRx® offers an unprecedented, global view of selectivity with the largest commercial panels, consisting of 456 kinase and 220 GPCR assays that can identify unanticipated off-target binding, which otherwise could be missed by smaller assay panels. Combined with additional pharmacological and toxicological data, kinome- or GPCRome-wide annotation provides important information about potential off-target liabilities to support selection of superior drug candidates with the best chance for future clinical success.

RSK Inhibitor BI-D1870
Selectivity of RSK inhibitor BI-D1870 was reported to be a selective RSK kinase inhibitor on the basis of kinase profiling against a panel of 54 kinases.  Selectivity profiling against the scanMAX kinase assay panel (then 402) revealed additional interactions not previously identified [click graph to enlarge].

Advantages of DiscoveRx’s Safety & Liability Screening Services

  • Trusted quality & service
  • Flexibility to build custom panels or profile against the full gpcrMAX & KINOMEscan® panels
  • Guide understanding of potential off-target liabilities, with broad selectivity information
  • Build knowledge base with information on selectivity, potency, & toxicity SAR

To learn more, select one of the tabs below

KINOMEscan® 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.

Services & Solutions

The largest commercial kinase panel available, scanMAX contains a definitive set of 456 kinases covering AGC, CAMK, CMGC, CK1, STE, TK, TKL, lipid and atypical kinase families, plus important mutant forms.


KdELECT

Quantitate compound binding affinity against any KINOMEscan® 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

Panel Size matters - effect of kinase panel size on apparent 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

Jak2 Inhibitor small panel versus large panel selectivity
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

RSK inhibitor small panel versus large panel selectivity
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].

The tendency of small molecules to interact with multiple GPCRs 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 GPCRs may be important therapeutic targets in other diseases. GPCRscan enables global selectivity profiles to be determined using the largest commercial panel of functional GPCR assays.  By profiling against a broad range of GPCR targets, off-target effects can be easily uncovered which may have been missed using smaller assay panels.

Services & Solutions

gpcrmax

The largest commercial GPCR panel available, gpcrMAX contains a definitive set of 158 kinases covering 54 GPCR families. Learn more >


gpcrE-IC50

Quantitate compound potency against any GPCRscan™ functional cell-based assay.  Agonist half maximal effective concentrations (EC50s) and antagonist half maximal inhibitory concentrations (IC50s) are calculated from duplicate 10-point dose-response curves.  Measurements are made under optimized conditions to generate consistent and reproducible data that reliably reflects the drug’s potency. Learn more >

View Complete List of GPCR Targets Available for Safety & Liability Screening