Modulating multi-functional ERK complexes by covalent targeting of a recruitment site in vivo
| Autor: | Kevin N. Dalby, Matthew Harger, Kenneth Y. Tsai, Pengyu Ren, Rachel M. Sammons, Tamer S. Kaoud, Clint D.J. Tavares, Jacey R. Pridgen, Ramakrishna Edupuganti, Mohamed F. Radwan, Diana Zamora-Olivares, Nancy D. Ebelt, Sabrina X. Van Ravenstein, Eric V. Anslyn, Mangalika Warthaka, Jihyun Park, Micael Cano, William H. Johnson, Ranajeet Ghose, Andrea Piserchio |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Cell cycle checkpoint General Physics and Astronomy Apoptosis medicine.disease_cause Dioxanes 0302 clinical medicine lcsh:Science Melanoma Mitogen-Activated Protein Kinase 1 Mutation Multidisciplinary Molecular medicine biology Chemistry MEK inhibitor Small molecule 3. Good health Cell biology 030220 oncology & carcinogenesis Protein Binding MAP Kinase Signaling System Science Mice Nude Kinases Drug development Mechanism of action Molecular Dynamics Simulation Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Cell Line Tumor medicine Animals Humans Cysteine Protein Kinase Inhibitors Binding Sites HEK 293 cells Active site General Chemistry Xenograft Model Antitumor Assays Thiazoles HEK293 Cells 030104 developmental biology biology.protein lcsh:Q |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-15 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. The ERK signalling pathway is activated in many cancers, however ERK1 and ERK2 are difficult to target pharmacologically. Here, the authors identify a small molecule inhibitor that binds covalently to the D-recruitment site of ERK and induces cell death and reduces tumour growth in mice. |
| Databáze: | OpenAIRE |
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