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. 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 and Kevin N. Dalby ()
Additional contact information
Tamer S. Kaoud: The University of Texas at Austin
William H. Johnson: The University of Texas at Austin
Nancy D. Ebelt: The University of Texas at Austin
Andrea Piserchio: The City College of New York
Diana Zamora-Olivares: The University of Texas at Austin
Sabrina X. Ravenstein: The University of Texas at Austin
Jacey R. Pridgen: The University of Texas at Austin
Ramakrishna Edupuganti: The University of Texas at Austin
Rachel Sammons: The University of Texas at Austin
Micael Cano: The University of Texas at Austin
Mangalika Warthaka: The University of Texas at Austin
Matthew Harger: The University of Texas at Austin
Clint D. J. Tavares: Harvard Medical School
Jihyun Park: The University of Texas MD Anderson Cancer Center
Mohamed F. Radwan: King Abdulaziz University
Pengyu Ren: The University of Texas at Austin
Eric V. Anslyn: The University of Texas at Austin
Kenneth Y. Tsai: Moffitt Cancer Center
Ranajeet Ghose: The City College of New York
Kevin N. Dalby: The University of Texas at Austin

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12996-8

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