Strategy Tags Molecules' Protein Targets

A new nature-inspired strategy should make it easier to identify the protein targets of bioactive small molecules in living systems (Nat. Biotech., published online Oct. 2, dx.doi.org/10.1038/nbt1149).

Identifying the protein target of a “hit” from a chemical genomics screen remains a formidable challenge, particularly in mammalian systems. To overcome this technological hurdle, Benjamin F. Cravatt and coworkers at Scripps Research Institute have created structurally diverse libraries of small molecules (shown) that feature a protein-reactive spiroepoxide electrophile found in a number of natural products and an alkyne “click chemistry” handle for downstream enrichment of labeled proteins.

The researchers compare the proteome reactivity of library members that elicit a desired biological effect in a cell-based screen to identify proteins uniquely labeled by a given bioactive compound. They demonstrate the strategy’s utility by identifying a library member that inhibits breast cancer cell proliferation and fingering its protein target.

Cravatt notes that while the method might not yield good drugs, it provides critical guidance about viable therapeutic targets.