Polypharmacology has key advantages for a host of diseases including cancer, diabetes, and Mendelian diseases. Recent data supports the view that multi-targeting drugs can show increased efficacy, reduced toxicity, and in the case of cancer reduced susceptibility to emergent resistance. However, we are currently limited in our ability to predict chemical structures that are able to directly bind and inhibit multiple targets.

In this DREAM challenge, we seek new approaches to predicting the structures of candidates that can bind to and inhibit activity of multiple independent targets. Recent genetic and chemical dissection of models of medullary thyroid carcinoma have identified key targets that together strongly reduce the ability of oncogenic Ret(M918T) to transform cells: RET, SRC, BRAF; MKNK1 and others were identified as ‘anti-targets’ (Sonoshita et al, submitted). Overall, these polypharmacological approaches represent an exciting alternative to the single-targeted drugs currently being developed.

We will ask Challenge participants to use available databases, public and private, to predict compounds that bind multiple targets. Predictions that take new and promising approaches to drug/multi-target binding will be considered for testing in in vitro and/or in vivo assays.

Anticipated outcomes include: 1) Novel and re-usable methods for rational design of multi-targeting compounds and 2) a benchmark standard for assessing multi-targeting compounds.