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

Tamer S Kaoud; William H Johnson; Nancy D Ebelt; Andrea Piserchio; Diana Zamora-Olivares; Sabrina X Van Ravenstein; Jacey R Pridgen; Ramakrishna Edupuganti; Rachel Sammons; Micael Cano; Mangalika Warthaka; Matthew Harger; Clint D J Tavares; Jihyun Park; Mohamed F Radwan; Pengyu Ren; Eric V Anslyn; Kenneth Y Tsai; Ranajeet Ghose; Kevin N Dalby

doi:10.1038/s41467-019-12996-8

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.

Authors

Tamer S Kaoud^{1

2}, William H Johnson¹, Nancy D Ebelt¹, Andrea Piserchio³, Diana Zamora-Olivares⁴, Sabrina X Van Ravenstein¹, Jacey R Pridgen¹, Ramakrishna Edupuganti¹, Rachel Sammons¹, Micael Cano¹, Mangalika Warthaka¹, Matthew Harger⁵, Clint D J Tavares⁶, Jihyun Park⁷, Mohamed F Radwan⁸, Pengyu Ren⁵, Eric V Anslyn⁴, Kenneth Y Tsai⁹, Ranajeet Ghose^{3

10}, Kevin N Dalby¹¹

Affiliations

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. [email protected].

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.

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*

Substances

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

Grants and funding

R01 GM123252/GM/NIGMS NIH HHS/United States