Modulating multi-functional ERK complexes by covalent targeting of a recruitment site in vivo
Year: 2019
Type: article
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.
Source: Nature Communications
Authors: 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
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: U.S. Department of Health and Human Services, Carnegie Corporation of New York, Welch Foundation, Cancer Prevention and Research Institute of Texas, City University of New York, University of Texas at Austin, Advanced Storage Research Consortium, National Institutes of Health, University of California, San Francisco, University of Massachusetts Amherst, National Institute of General Medical Sciences
Awards: Targeted Therapeutic Drug Discovery & Development Program, G1907146399, G32849938, G340396948, G4815039349, G52711424, Regulation of eEF-2K an Energy and Nutrient Sensor, G6252650861, G6285642246, G694366315, G7613479429, Targeting BRAF- and RAS-Mutant Cancers by Small Molecule-Induced Proteolysis of ERK1/2, G858087134, G9000001160, G9000094659, G9000191919, G9000323318
OpenAlex ID: W2990996987