Abstract
Src-family kinases (SFKs) play important roles in human biology and are key drug targets as well. However, achieving selective inhibition of individual Src-family kinases is challenging due to the high similarity within the protein family. We describe rhodium(ii) conjugates that deliver both potent and selective inhibition of Src-family SH3 domains. Rhodium(ii) conjugates offer dramatic affinity enhancements due to interactions with specific and unique Lewis-basic histidine residues near the SH3 binding interface, allowing predictable, structure-guided inhibition of SH3 targets that are recalcitrant to traditional inhibitors. In one example, a simple metallopeptide binds the Lyn SH3 domain with 6 nM affinity and exhibits functional activation of Lyn kinase under biologically relevant concentrations (EC50 ∼ 200 nM).
Original language | English (US) |
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Pages (from-to) | 4778-4783 |
Number of pages | 6 |
Journal | Chemical Science |
Volume | 6 |
Issue number | 8 |
DOIs | |
State | Published - Aug 1 2015 |
ASJC Scopus subject areas
- General Chemistry