Identification and validation of selective deubiquitinase inhibitors.
Identification and validation of selective deubiquitinase inhibitors.
复制标题
选择性去泛素酶抑制剂的鉴定和验证。
DOI：
10.1016/j.chembiol.2021.05.012
复制
发表时间：
2021-12-16
影响因子：
8.6
通讯作者：
Buhrlage, Sara J.
中科院分区：
文献类型：
--
作者：
Varca, Anthony C.;Casalena, Dominick;Chan, Wai Cheung;Hu, Bin;Magin, Robert S.;Roberts, Rebekka M.;Liu, Xiaoxi;Zhu, He;Seo, Hyuk-Soo;Dhe-Paganon, Sirano;Marto, Jarrod A.;Auld, Douglas;Buhrlage, Sara J.
去泛素化酶（DUBs）是一类通过催化泛素从蛋白质底物和泛素前体裂解来调节泛素动力学的异肽酶。尽管对DUB生物学功能和作为治疗靶点的潜力的兴趣越来越大，但目前存在很少的选择性小分子抑制剂和没有批准的药物。为了鉴定靶向特定DUB的化学支架，并为跨基因家族的未来抑制剂开发建立更广泛的框架，我们对8种不同DUB的化学多样性小分子文库进行了高通量筛选，这些DUB跨越了3个充分表征的DUB家族。在一系列反筛选和正交测定中验证有希望的命中化合物，并进一步评估扩大的DUB组之间的选择性。通过这些努力，我们已经确定了多种高选择性DUB抑制剂，并开发了快速识别和验证相关酶的选择性抑制剂的路线图。去泛素化酶（DUB）由于参与细胞中的蛋白质周转而成为治疗上令人感兴趣的靶标。瓦尔卡等等人描述了多DUB高通量筛选和正交验证活动，以鉴定用于阐明DUB功能的新工具化合物，并为未来的DUB抑制剂筛选提供路线图。
Deubiquitinating enzymes (DUBs) are a class of isopeptidases that regulate ubiquitin dynamics through catalytic cleavage of ubiquitin from protein substrates and ubiquitin precursors. Despite growing interest in DUB biological function and potential as therapeutic targets, few selective small molecule inhibitors and no approved drugs currently exist. To identify chemical scaffolds targeting specific DUBs and establish a broader framework for future inhibitor development across the gene-family, we performed high-throughput screening of a chemically diverse small molecule library against eight different DUBs, spanning three well-characterized DUB families. Promising hit compounds were validated in a series of counter-screens and orthogonal assays, as well as further assessed for selectivity across expanded panels of DUBs. Through these efforts, we have identified multiple highly selective DUB inhibitors and developed a roadmap for rapidly identifying and validating selective inhibitors of related enzymes. Deubiquitinases (DUBs) have emerged as therapeutically interesting targets due to their involvement in protein turnover in cells. Varca et. al. describe a multi-DUB high throughput screen and orthogonal validation campaign to identify new tool compounds for elucidating DUB function and provide a roadmap for future DUB inhibitor screens.
登录
查看更多内容
DOI：
10.1038/nrd.2017.152
发表时间：
2018-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Harrigan JA;Jacq X;Martin NM;Jackson SP
通讯作者：
Jackson SP
影响因子：
16.6
作者：
Hermanns T;Pichlo C;Woiwode I;Klopffleisch K;Witting KF;Ovaa H;Baumann U;Hofmann K
通讯作者：
Hofmann K
影响因子：
5.7
作者：
Ding WX;Ni HM;Gao W;Chen X;Kang JH;Stolz DB;Liu J;Yin XM
通讯作者：
Yin XM
影响因子：
4.6
作者：
Daina A;Michielin O;Zoete V
通讯作者：
Zoete V
影响因子：
16
作者：
Haahr, Peter;Borgermann, Nikoline;Mailand, Niels
通讯作者：
Mailand, Niels