التفاصيل البيبلوغرافية
| العنوان: |
Optimization and Anti-Cancer Properties of Fluoromethylketones as Covalent Inhibitors for Ubiquitin C-Terminal Hydrolase L1 |
| المؤلفون: |
Aaron D. Krabill, Hao Chen, Sajjad Hussain, Chad S. Hewitt, Ryan D. Imhoff, Christine S. Muli, Chittaranjan Das, Paul J. Galardy, Michael K. Wendt, Daniel P. Flaherty |
| المصدر: |
Molecules; Volume 26; Issue 5; Pages: 1227 |
| بيانات النشر: |
Multidisciplinary Digital Publishing Institute |
| سنة النشر: |
2021 |
| المجموعة: |
MDPI Open Access Publishing |
| مصطلحات موضوعية: |
covalent inhibitors, fluoromethylketones, UCHL1 inhibitors, deubiquitinases |
| جغرافية الموضوع: |
agris |
| الوصف: |
The deubiquitinating enzyme (DUB) UCHL1 is implicated in various disease states including neurodegenerative disease and cancer. However, there is a lack of quality probe molecules to gain a better understanding on UCHL1 biology. To this end a study was carried out to fully characterize and optimize the irreversible covalent UCHL1 inhibitor VAEFMK. Structure-activity relationship studies identified modifications to improve activity versus the target and a full cellular characterization was carried out for the first time with this scaffold. The studies produced a new inhibitor, 34, with an IC50 value of 7.7 µM against UCHL1 and no observable activity versus the closest related DUB UCHL3. The molecule was also capable of selectively inhibiting UCHL1 in cells and did not demonstrate any discernible off-target toxicity. Finally, the molecule was used for initial probe studies to assess the role of UCHL1 role in proliferation of myeloma cells and migration behavior in small cell lung cancer cells making 34 a new tool to be used in the biological evaluation of UCHL1. |
| نوع الوثيقة: |
text |
| وصف الملف: |
application/pdf |
| اللغة: |
English |
| العلاقة: |
Medicinal Chemistry; https://dx.doi.org/10.3390/molecules26051227Test |
| DOI: |
10.3390/molecules26051227 |
| الإتاحة: |
https://doi.org/10.3390/molecules26051227Test |
| حقوق: |
https://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: |
edsbas.4204766E |
| قاعدة البيانات: |
BASE |
