Modulating multi-functional ERK complexes by covalent targeting of a recruitment site in vivo

Nat Commun. 2019 Nov 19;10(1):5232. doi: 10.1038/s41467-019-12996-8.


Recently, the targeting of ERK with ATP-competitive inhibitors has emerged as a potential clinical strategy to overcome acquired resistance to BRAF and MEK inhibitor combination therapies. In this study, we investigate an alternative strategy of targeting the D-recruitment site (DRS) of ERK. The DRS is a conserved region that lies distal to the active site and mediates ERK-protein interactions. We demonstrate that the small molecule BI-78D3 binds to the DRS of ERK2 and forms a covalent adduct with a conserved cysteine residue (C159) within the pocket and disrupts signaling in vivo. BI-78D3 does not covalently modify p38MAPK, JNK or ERK5. BI-78D3 promotes apoptosis in BRAF inhibitor-naive and resistant melanoma cells containing a BRAF V600E mutation. These studies provide the basis for designing modulators of protein-protein interactions involving ERK, with the potential to impact ERK signaling dynamics and to induce cell cycle arrest and apoptosis in ERK-dependent cancers.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Binding Sites / genetics
  • Cell Line, Tumor
  • Cysteine / genetics
  • Cysteine / metabolism
  • Dioxanes / metabolism
  • Dioxanes / pharmacology*
  • HEK293 Cells
  • Humans
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / genetics
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / metabolism
  • Mice, Nude
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Molecular Dynamics Simulation
  • Protein Binding / drug effects
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Thiazoles / metabolism
  • Thiazoles / pharmacology*
  • Xenograft Model Antitumor Assays*


  • 4-(2,3-dihydro-1,4-benzodioxin-6-yl)-2,4-dihydro-5-((5-nitro-2-thiazolyl)thio)-3H-1,2,4-triazol-3-one
  • Dioxanes
  • Protein Kinase Inhibitors
  • Thiazoles
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Cysteine