Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, 575 Stadium Mall Dr., West Lafayette, IN 47907, USA.
Division of Pediatric Hematology-Oncology, Mayo Clinic, 200 First St. Guggenheim 15, Rochester, MN 55905, USA.
Molecules. 2021 Feb 25;26(5):1227. doi: 10.3390/molecules26051227.
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, , with an IC 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 a new tool to be used in the biological evaluation of UCHL1.
去泛素化酶（DUB）UCHL1 与多种疾病状态有关，包括神经退行性疾病和癌症。然而，目前缺乏高质量的探针分子来更好地了解 UCHL1 的生物学特性。为此，进行了一项研究，以充分表征和优化不可逆共价 UCHL1 抑制剂 VAEFMK。构效关系研究确定了对提高活性的修饰，这是该支架首次进行全面的细胞特征描述。研究产生了一种新的抑制剂 ，对 UCHL1 的 IC 值为 7.7µM，对最接近的相关 DUB UCHL3 没有可观察到的活性。该分子还能够在细胞中选择性地抑制 UCHL1，并且没有表现出任何可察觉的脱靶毒性。最后，该分子被用于初步的探针研究，以评估 UCHL1 在骨髓瘤细胞增殖和小细胞肺癌细胞迁移行为中的作用，为 UCHL1 的生物学评估提供了一个新的工具。
