bei Google ScholarTitelangaben
Henschke, Lars ; Frese, Matthias ; Hellmuth, Susanne ; Marx, Andreas ; Stemmann, Olaf ; Mayer, Thomas U.:
Identification of Bioactive Small Molecule Inhibitors of Separase.
In: ACS Chemical Biology.
Bd. 14
(2019)
Heft 10
.
- S. 2155-2159.
ISSN 1554-8937
DOI: https://doi.org/10.1021/acschembio.9b00661
Abstract
Separase, a cysteine protease of the CD clan, triggers chromosome segregation during mitosis by cleaving the cohesin ring entrapping the two sister chromatids. Deregulated separase activity is associated with aneuploidy, a hallmark of most human cancers. In fact, separase is highly overexpressed in many solid cancers, making it an attractive chemotherapeutic target. To identify small molecules capable of inhibiting separase in its complex cellular environment, we established a highly sensitive assay to quantify separase activity in cells and screened a 51 009-member library for separase inhibitors. In vitro assays confirmed that the identified compounds efficiently inhibited separase, while not affecting caspase-1, another CD-clan protease structurally related to separase. Importantly, HeLa cells with compromised separase activity displayed severe chromosome segregation defects upon compound treatment, confirming that the identified inhibitors are bioactive in tumor tissue culture cells. Structure-activity relationship studies succeeded in the optimization of the most promising inhibitor. Overall, this study demonstrates the feasibility of identifying separase-specific inhibitors, which serve as promising lead compounds for the development of clinically relevant separase inhibiting drugs.
Weitere Angaben
| Publikationsform: | Artikel in einer Zeitschrift |
|---|---|
| Begutachteter Beitrag: | Ja |
| Keywords: | COHESIN CLEAVAGE; OVEREXPRESSION; ANEUPLOIDY |
| Institutionen der Universität: | Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Biologie > Lehrstuhl Genetik > Lehrstuhl Genetik - Univ.-Prof. Dr. Olaf Stemmann Fakultäten Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Biologie Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Biologie > Lehrstuhl Genetik |
| Titel an der UBT entstanden: | Ja |
| Themengebiete aus DDC: | 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften; Biologie |
| Eingestellt am: | 26 Feb 2020 09:23 |
| Letzte Änderung: | 19 Okt 2022 11:46 |
| URI: | https://eref.uni-bayreuth.de/id/eprint/54404 |