Drug repositioning holds a tremendous potential to cost-effectively explore drugs with favorable pharmacokinetics and safety profiles for emerging targets. Here we utilized novel integrative modeling approaches to identify new therapeutic indications for several FDA-approved drugs against an unexploited colorectal cancer target, TNIK. We first collected a dataset of 102 compounds with known TNIK activities and performed molecular docking against TNIK. Based on the alignment of their docked poses, we derived QSAR models using CoMSIA and kNN methods. Using these models, we identified a set of drugs (e.g., sunitinib) which strongly inhibit TNIK activities upon screening of 1,448 FDA-approved small-molecule drugs. These predictions were further validated using the KINOMEscan profiling platform, confirming that their binding affinities (e.g., Kd) to TNIK are in the range of 10�M~50nM. The subsequent modeling analyses proved that these agents acquires favorable molecular characteristics to inhibit TNIK kinase activities.

Drug repositioning for discovery of novel TRAF2 and NCK-interacting kinase (TNIK) inhibitors

246th National Meeting (2013)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.