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Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors.


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).

SUBMITTER: Vohidov F 

PROVIDER: S-EPMC5667506 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors.

Vohidov Farrukh F   Knudsen Sarah E SE   Leonard Paul G PG   Ohata Jun J   Wheadon Michael J MJ   Popp Brian V BV   Ladbury John E JE   Ball Zachary T ZT  

Chemical science 20150603 8


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  ...[more]

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