Optimization and Anti-Cancer Properties of Fluoromethylketones as Covalent Inhibitors for Ubiquitin C-Terminal Hydrolase L1.
Optimization and Anti-Cancer Properties of Fluoromethylketones as Covalent Inhibitors for Ubiquitin C-Terminal Hydrolase L1.
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DOI：
10.3390/molecules26051227
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发表时间：
2021-02-25
期刊：
影响因子：
--
通讯作者：
Flaherty DP
中科院分区：
文献类型：
--
作者：
Krabill AD;Chen H;Hussain S;Hewitt CS;Imhoff RD;Muli CS;Das C;Galardy PJ;Wendt MK;Flaherty DP
脱泛素酶(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，目前还缺乏高质量的探针分子来更好地了解UCHL1生物学。为此，开展了一项研究，以充分表征和优化不可逆共价UCHL1抑制剂VAEFMK。结构-活性关系研究确定了修饰以提高活性相对于目标，并首次在这种支架上进行了全面的细胞表征。这些研究产生了一种新的抑制剂34，对UCHL1的IC50值为7.7微米，与最接近的UCHL3相比没有可观察到的活性。该分子还能够选择性地抑制细胞中的UCHL1，并且没有表现出任何明显的脱靶毒性。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，使34成为用于UCHL1生物学评估的新工具。
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.
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影响因子：
4.8
作者：
Garcia-Calvo, M;Peterson, EP;Thornberry, NA
通讯作者：
Thornberry, NA
影响因子：
4.8
作者：
Atkin G;Paulson H
通讯作者：
Paulson H
DOI：
10.1074/jbc.m114.557124
发表时间：
2014-12-26
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Bishop P;Rubin P;Thomson AR;Rocca D;Henley JM
通讯作者：
Henley JM
DOI：
10.1042/bcj20160082
发表时间：
2016-08-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Bishop P;Rocca D;Henley JM
通讯作者：
Henley JM
影响因子：
2.6
作者：
Jara, Javier H.;Frank, Dominic D.;Oezdinler, P. Hande
通讯作者：
Oezdinler, P. Hande