Highly Specific, Bi-substrate-Competitive Src Inhibitors from DNA-Templated Macrocycles

DSpace/Manakin Repository

Highly Specific, Bi-substrate-Competitive Src Inhibitors from DNA-Templated Macrocycles

Citable link to this page

 

 
Title: Highly Specific, Bi-substrate-Competitive Src Inhibitors from DNA-Templated Macrocycles
Author: Georghiou, George; Kleiner, Ralph E.; Pulkoski-Gross, Michael; Liu, David Ruchien; Seeliger, Markus A.

Note: Order does not necessarily reflect citation order of authors.

Citation: Georghiou, George, Ralph E. Kleiner, Michael Pulkoski-Gross, David R. Liu, and Markus A. Seeliger. 2011. Highly specific, bi-substrate-competitive src inhibitors from dna-templated macrocycles. Nature Chemical Biology 8(4): 366-374.
Full Text & Related Files:
Abstract: Protein kinases are attractive therapeutic targets, but their high sequence and structural conservation complicates the development of specific inhibitors. We recently discovered from a DNA-templated macrocycle library inhibitors with unusually high selectivity among Src-family kinases. Starting from these compounds, we developed and characterized in molecular detail potent macrocyclic inhibitors of Src kinase and its cancer-associated gatekeeper mutant. We solved two co-crystal structures of macrocycles bound to Src kinase. These structures reveal the molecular basis of the combined ATP- and substrate peptide-competitive inhibitory mechanism and the remarkable kinase specificity of the compounds. The most potent compounds inhibit Src activity in cultured mammalian cells. Our work establishes that macrocycles can inhibit protein kinases through a bi-substrate competitive mechanism with high potency and exceptional specificity, reveals the precise molecular basis for their desirable properties, and provides new insights into the development of Src-specific inhibitors with potential therapeutic relevance.
Published Version: doi:10.1038/nchembio.792
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3307835/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:11726263
Downloads of this work:

Show full Dublin Core record

This item appears in the following Collection(s)

 
 

Search DASH


Advanced Search
 
 

Submitters