Structural and Biochemical Basis for Intracellular Kinase Inhibition by Src-specific Peptidic Macrocycles

Saadat U. Aleem, George Georghiou, Ralph E. Kleiner, Kip E. Guja, Barbara P. Craddock, Agatha Lyczek, Alix I. Chan, Miguel Garcia-Diaz, W. Todd Miller, David R. Liu, Markus A. Seeliger

Research output: Contribution to journalArticle

8 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1103-1112
Number of pages10
JournalCell Chemical Biology
Volume23
Issue number9
DOIs
StatePublished - Sep 22 2016

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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    Aleem, S. U., Georghiou, G., Kleiner, R. E., Guja, K. E., Craddock, B. P., Lyczek, A., Chan, A. I., Garcia-Diaz, M., Miller, W. T., Liu, D. R., & Seeliger, M. A. (2016). Structural and Biochemical Basis for Intracellular Kinase Inhibition by Src-specific Peptidic Macrocycles. Cell Chemical Biology, 23(9), 1103-1112. https://doi.org/10.1016/j.chembiol.2016.07.017