Parthenolide Covalently Targets and Inhibits Focal Adhesion Kinase in Breast Cancer Cells

Cell Chem Biol. 2019 Jul 18;26(7):1027-1035.e22. doi: 10.1016/j.chembiol.2019.03.016. Epub 2019 May 9.


Parthenolide, a natural product from the feverfew plant and member of the large family of sesquiterpene lactones, exerts multiple biological and therapeutic activities including anti-inflammatory and anti-cancer effects. Here, we further study the parthenolide mechanism of action using activity-based protein profiling-based chemoproteomic platforms to map additional covalent targets engaged by parthenolide in human breast cancer cells. We find that parthenolide, as well as other related exocyclic methylene lactone-containing sesquiterpenes, covalently modify cysteine 427 of focal adhesion kinase 1 (FAK1), leading to impairment of FAK1-dependent signaling pathways and breast cancer cell proliferation, survival, and motility. These studies reveal a functional target exploited by members of a large family of anti-cancer natural products.

Keywords: ABPP; FAK1; PTK2; activity-based protein profiling; chemoproteomics; covalent ligands; focal adhesion kinase 1; natural products; parthenolide.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Products
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Female
  • Focal Adhesion Kinase 1 / antagonists & inhibitors
  • Focal Adhesion Kinase 1 / metabolism*
  • Focal Adhesion Protein-Tyrosine Kinases
  • Humans
  • Lactones
  • Sesquiterpenes / metabolism*
  • Sesquiterpenes / pharmacology
  • Signal Transduction / drug effects
  • Tanacetum parthenium


  • Biological Products
  • Lactones
  • Sesquiterpenes
  • methylene-lactone
  • parthenolide
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • PTK2 protein, human