Modulating multi-functional ERK complexes by covalent targeting of a recruitment site in vivo.
Animals
Apoptosis
/ drug effects
Binding Sites
/ genetics
Cell Line, Tumor
Cysteine
/ genetics
Dioxanes
/ metabolism
HEK293 Cells
Humans
MAP Kinase Signaling System
/ drug effects
Melanoma
/ drug therapy
Mice, Nude
Mitogen-Activated Protein Kinase 1
/ antagonists & inhibitors
Molecular Dynamics Simulation
Protein Binding
/ drug effects
Protein Kinase Inhibitors
/ metabolism
Thiazoles
/ metabolism
Xenograft Model Antitumor Assays
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
19 11 2019
19 11 2019
Historique:
received:
12
01
2019
accepted:
10
10
2019
entrez:
21
11
2019
pubmed:
21
11
2019
medline:
10
3
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31745079
doi: 10.1038/s41467-019-12996-8
pii: 10.1038/s41467-019-12996-8
pmc: PMC6863825
doi:
Substances chimiques
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
0
Dioxanes
0
Protein Kinase Inhibitors
0
Thiazoles
0
MAPK1 protein, human
EC 2.7.11.24
Mitogen-Activated Protein Kinase 1
EC 2.7.11.24
Cysteine
K848JZ4886
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5232Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM123252
Pays : United States
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