Treatment-emergent mutations in NAEβ confer resistance to the NEDD8-activating enzyme inhibitor MLN4924
Autor: | Xiaofeng Yang, Michael Milhollen, Neil Bence, Mark Manfredi, Huay-Keng Loke, Erik Koenig, James E. Brownell, Mike Sintchak, Michael P. Thomas, Usha Narayanan, Qing Xu, James M. Gavin, Jessica Riceberg, Alice McDonald, Joseph B. Bolen, Benjamin S. Amidon, Peter G. Smith, Sells Todd B, Tary Traore, Jingya Ma, Lawrence R. Dick |
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Rok vydání: | 2011 |
Předmět: |
Cancer Research
Mutant Mice Nude Cyclopentanes Ubiquitin-Activating Enzymes Biology Adduct Protein neddylation chemistry.chemical_compound Mice Rats Nude Cell Line Tumor NEDD8 Activating Enzyme medicine Tumor Cells Cultured Animals Humans Enzyme Inhibitors chemistry.chemical_classification Clinical Trials as Topic Binding Sites Cancer Cell Biology medicine.disease Molecular biology Xenograft Model Antitumor Assays Rats Enzyme Pevonedistat Pyrimidines chemistry Biochemistry Oncology Drug Resistance Neoplasm Mutation Female Adenosine triphosphate |
Zdroj: | Cancer cell. 21(3) |
ISSN: | 1878-3686 |
Popis: | SummaryMLN4924 is an investigational small-molecule inhibitor of NEDD8-activating enzyme (NAE) in clinical trials for the treatment of cancer. MLN4924 is a mechanism-based inhibitor, with enzyme inhibition occurring through the formation of a tight-binding NEDD8-MLN4924 adduct. In cell and xenograft models of cancer, we identified treatment-emergent heterozygous mutations in the adenosine triphosphate binding pocket and NEDD8-binding cleft of NAEβ as the primary mechanism of resistance to MLN4924. Biochemical analyses of NAEβ mutants revealed slower rates of adduct formation and reduced adduct affinity for the mutant enzymes. A compound with tighter binding properties was able to potently inhibit mutant enzymes in cells. These data provide rationales for patient selection and the development of next-generation NAE inhibitors designed to overcome treatment-emergent NAEβ mutations. |
Databáze: | OpenAIRE |
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