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

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

Author information

1
Division of Chemical Biology and Medicinal Chemistry, The University of Texas at Austin, Austin, TX, 78712, USA.
2
Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt.
3
Department of Chemistry and Biochemistry, The City College of New York, New York, NY, USA.
4
Department of Chemistry, The University of Texas at Austin, Austin, TX, 78712, USA.
5
Biomedical Engineering Department, The University of Texas at Austin, Austin, TX, USA.
6
Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA.
7
The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
8
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, 21589, Saudi Arabia.
9
Moffitt Cancer Center, Tampa, FL, USA.
10
Graduate Programs in Biochemistry, Chemistry and Physics, The Graduate Center of the City University of New York, New York, NY, 10016, USA.
11
Division of Chemical Biology and Medicinal Chemistry, The University of Texas at Austin, Austin, TX, 78712, USA. dalby@austin.utexas.edu.

Abstract

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.

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