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Identification of Bioactive Small Molecule Inhibitors of Separase

Title data

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. Vol. 14 (October 2019) Issue 10 . - pp. 2155-2159.
ISSN 1554-8937
DOI: https://doi.org/10.1021/acschembio.9b00661

Abstract in another language

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.

Further data

Item Type: Article in a journal
Refereed: Yes
Keywords: COHESIN CLEAVAGE; OVEREXPRESSION; ANEUPLOIDY
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Biology > Chair Genetics > Chair Genetics - Univ.-Prof. Dr. Olaf Stemmann
Result of work at the UBT: Yes
DDC Subjects: 500 Science > 570 Life sciences, biology
Date Deposited: 26 Feb 2020 09:23
Last Modified: 26 Feb 2020 09:23
URI: https://eref.uni-bayreuth.de/id/eprint/54404