ArticleCell chemical biology2016
Structural and Biochemical Basis for Intracellular Kinase Inhibition by Src-specific Peptidic Macrocycles.
Article in Cell chemical biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 14 citations in OpenAlex.
- Structural insight into the macrocyclic inhibitor TPX-0022 of c-Met and c-Src.Computational and structural biotechnology journal · 2023Article
- Targeting Dynamic ATP-Binding Site Features Allows Discrimination between Highly Homologous Protein Kinases.ACS chemical biology · 2019Article
- Crystal structures of green fluorescent protein with the unnatural amino acid 4-nitro-L-phenylalanine.Acta crystallographica. Section F, Structural biology communications · 2018Article
- Second-generation DNA-templated macrocycle libraries for the discovery of bioactive small molecules.Nature chemistry · 2018Article
- Selective targeting of the inactive state of hematopoietic cell kinase (Hck) with a stable curcumin derivative.The Journal of biological chemistryArticle
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Protein kinases are attractive therapeutic targets because their dysregulation underlies many diseases, including cancer. The high conservation of the kinase domain and the evolution of drug resistance, however, pose major challenges to the development of specific kinase inhibitors. We recently discovered selective Src kinase inhibitors from a DNA-templated macrocycle library. Here, we reveal the structural basis for how these inhibitors retain activity against a disease-relevant, drug-resistant kinase mutant, while maintaining Src specificity. We find that these macrocycles display a degree of modularity: two of their three variable groups interact with sites on the kinase that confer selectivity, while the third group interacts with the universally conserved catalytic lysine and thereby retains the ability to inhibit the "gatekeeper" kinase mutant. We also show that these macrocycles inhibit migration of MDA-MB-231 breast tumor cells. Our findings establish intracellular kinase inhibition by peptidic macrocycles, and inform the development of potent and specific kinase inhibitors.
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Registered trials
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