Abstract |
MLN4924 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.
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Authors | Michael A Milhollen, Michael P Thomas, Usha Narayanan, Tary Traore, Jessica Riceberg, Benjamin S Amidon, Neil F Bence, Joseph B Bolen, James Brownell, Lawrence R Dick, Huay-Keng Loke, Alice A McDonald, Jingya Ma, Mark G Manfredi, Todd B Sells, Mike D Sintchak, Xiaofeng Yang, Qing Xu, Erik M Koenig, James M Gavin, Peter G Smith |
Journal | Cancer cell
(Cancer Cell)
Vol. 21
Issue 3
Pg. 388-401
(Mar 20 2012)
ISSN: 1878-3686 [Electronic] United States |
PMID | 22439935
(Publication Type: Journal Article)
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Copyright | Copyright © 2012 Elsevier Inc. All rights reserved. |
Chemical References |
- Cyclopentanes
- Enzyme Inhibitors
- Pyrimidines
- Ubiquitin-Activating Enzymes
- pevonedistat
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Topics |
- Animals
- Binding Sites
- Cell Line, Tumor
- Clinical Trials as Topic
- Cyclopentanes
(pharmacology)
- Drug Resistance, Neoplasm
(genetics)
- Enzyme Inhibitors
(pharmacology)
- Female
- Humans
- Mice
- Mice, Nude
- Mutation
- Pyrimidines
(pharmacology)
- Rats
- Rats, Nude
- Tumor Cells, Cultured
- Ubiquitin-Activating Enzymes
(chemistry, genetics, physiology)
- Xenograft Model Antitumor Assays
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