دورية أكاديمية
Metabolically Labile Fumarate Esters Impart Kinetic Selectivity to Irreversible Inhibitors.
| العنوان: | Metabolically Labile Fumarate Esters Impart Kinetic Selectivity to Irreversible Inhibitors. |
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| المؤلفون: | Zaro BW; The Skaggs Institute for Chemical Biology and Department of Chemical Physiology , 10550 North Torrey Pines Road, La Jolla, California 92037, United States., Whitby LR; The Skaggs Institute for Chemical Biology and Department of Chemical Physiology , 10550 North Torrey Pines Road, La Jolla, California 92037, United States., Lum KM; The Skaggs Institute for Chemical Biology and Department of Chemical Physiology , 10550 North Torrey Pines Road, La Jolla, California 92037, United States., Cravatt BF; The Skaggs Institute for Chemical Biology and Department of Chemical Physiology , 10550 North Torrey Pines Road, La Jolla, California 92037, United States. |
| المصدر: | Journal of the American Chemical Society [J Am Chem Soc] 2016 Dec 14; Vol. 138 (49), pp. 15841-15844. Date of Electronic Publication: 2016 Dec 05. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 7503056 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5126 (Electronic) Linking ISSN: 00027863 NLM ISO Abbreviation: J Am Chem Soc Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington, DC : American Chemical Society Original Publication: Easton, Pa. [etc.] |
| مواضيع طبية MeSH: | Fumarates/*metabolism , Protein Kinase Inhibitors/*pharmacology , Protein-Tyrosine Kinases/*antagonists & inhibitors , Pyrazoles/*pharmacology , Pyrimidines/*pharmacology, Adenine/analogs & derivatives ; Cells, Cultured ; Fumarates/chemistry ; HEK293 Cells ; Humans ; Kinetics ; Molecular Structure ; Piperidines ; Protein Kinase Inhibitors/chemistry ; Protein-Tyrosine Kinases/metabolism ; Pyrazoles/chemistry ; Pyrazoles/metabolism ; Pyrimidines/chemistry ; Pyrimidines/metabolism ; Structure-Activity Relationship |
| مستخلص: | Electrophilic small molecules are an important class of chemical probes and drugs that produce biological effects by irreversibly modifying proteins. Examples of electrophilic drugs include covalent kinase inhibitors that are used to treat cancer and the multiple sclerosis drug dimethyl fumarate. Optimized covalent drugs typically inactivate their protein targets rapidly in cells, but ensuing time-dependent, off-target protein modification can erode selectivity and diminish the utility of reactive small molecules as chemical probes and therapeutics. Here, we describe an approach to confer kinetic selectivity to electrophilic drugs. We show that an analogue of the covalent Bruton's tyrosine kinase (BTK) inhibitor Ibrutinib bearing a fumarate ester electrophile is vulnerable to enzymatic metabolism on a time-scale that preserves rapid and sustained BTK inhibition, while thwarting more slowly accumulating off-target reactivity in cell and animal models. These findings demonstrate that metabolically labile electrophilic groups can endow covalent drugs with kinetic selectivity to enable perturbation of proteins and biochemical pathways with greater precision. |
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| معلومات مُعتمدة: | R01 CA087660 United States CA NCI NIH HHS; R37 CA087660 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Fumarates) 0 (Piperidines) 0 (Protein Kinase Inhibitors) 0 (Pyrazoles) 0 (Pyrimidines) 1X70OSD4VX (ibrutinib) EC 2.7.10.1 (Protein-Tyrosine Kinases) JAC85A2161 (Adenine) |
| تواريخ الأحداث: | Date Created: 20161215 Date Completed: 20180516 Latest Revision: 20211204 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC5273863 |
| DOI: | 10.1021/jacs.6b10589 |
| PMID: | 27960302 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-5126 |
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| DOI: | 10.1021/jacs.6b10589 |