Challenging the “Undruggable”Targeting STAT3 but Identifying Potent TrkA-Targeted Inhibitors

Signal transducer and activator of transcription 3 (STAT3)
is a
promising yet challenging anticancer drug target due to its complex
signaling and limited “druggability”. To this end, we
herein highlight a target engagement-focused screening and optimization
pipeline pursuing the discovery of novel STAT3 inhibitors. From a
STAT3 differential scanning fluorimetry high-throughput screen, we
identified compounds that appeared to stabilize STAT3 toward thermal
aggregation and moderately inhibited cellular STAT3 activity. Subsequent
evaluation using complementary and orthogonal assays revealed their
high affinity for tropomyosin receptor kinase A (TrkA). Applying a
similar target engagement-inspired approach, we refined inhibitor
binding and selectivity toward TrkA, showing efficacy in cellular
TrkA cancer models. Top compound, PI-15, demonstrated
successful target engagement in a cellular thermal shift assay and
potently inhibited TrkA activity in cancer cells. These approaches
highlight the importance of prioritizing rigorous target engagement
validation early in the drug discovery pipeline, resulting in promising
new inhibitors.