Preclinical/Animal Studies Assessment of In Vivo Target Engagement and Inhibitor Selectivity

KiNativ™ provides a powerful platform for accurately and efficiently tracking target engagement in treated animals from any tissue in essentially any animal model. Along with critical target potency information, these studies can also indicate relevant off-targets, as well as secondary pathway effects.

• Inhibitors A and B are JNK inhibitors with similar potency against JNK
• These inhibitors were selected for testing in the mouse acetaminophen (APAP)-induced liver injury model

Results from KiNativ™ Profiling

Target Engagement

Inhibitors A and B strongly inhibited JNK at one and six hours after APAP treatment at the 100 mg/kg dose (90% inhibition). At 30 mg/kg, inhibitor B demonstrated potent inhibition of JNK at one hour, but markedly reduced activity at six hours (90% versus 70% inhibition). This demonstrates the capacity of KiNativ™ to quantify in vivo target engagement at the relevant site of action. Moreover, the reduced JNK inhibition by inhibitor B at 30 mg/kg also correlated with a lack of in vivo efficacy as measured by serum ALT levels. Combined, these results indicate that KiNativ™ can quantify in vivo target engagement and is predictive of in vivo efficacy.