Development of a NanoBRET assay to validate inhibitors of Sirt2-mediated lysine deacetylation and defatty-acylation that block prostate cancer cell migration

Vogelmann A, Schiedel M, Woessner N, Merz A, Herp D, Hammelmann S, Colcerasa A, Komaniecki G, Hong JY, Sum M, Metzger E, Neuwirt E, Zhang L, Einsle O, Gross O, Schuele R, Lin H, Sippl W, Jung M (2022)

Publication Type: Journal article

Publication year: 2022

Journal

RSC Chemical Biology The Royal Society of Chemistry

DOI: 10.1039/d1cb00244a

Abstract

Sirtuin2 (Sirt2) with its NAD(+)-dependent deacetylase and defatty-acylase activities plays a central role in the regulation of specific cellular functions. Dysregulation of Sirt2 activity has been associated with the pathogenesis of many diseases, thus making Sirt2 a promising target for pharmaceutical intervention. Herein, we present new high affinity Sirt2 selective Sirtuin-Rearranging Ligands (SirReals) that inhibit both Sirt2-dependent deacetylation and defatty-acylation in vitro and in cells. We show that simultaneous inhibition of both Sirt2 activities results in strongly reduced levels of the oncoprotein c-Myc and an inhibition of cancer cell migration. Furthermore, we describe the development of a NanoBRET-based assay for Sirt2, thereby providing a method to study cellular target engagement for Sirt2 in a straightforward and accurately quantifiable manner. Applying this assay, we could confirm cellular Sirt2 binding of our new Sirt2 inhibitors and correlate their anticancer effects with their cellular target engagement.

Authors with CRIS profile

Matthias Schiedel Lehrstuhl für Pharmazeutische Chemie

Involved external institutions

Albert-Ludwigs-Universität Freiburg DE Germany (DE) Cornell University US United States (USA) (US) Martin-Luther-Universität Halle-Wittenberg (MLU) DE Germany (DE)

How to cite

APA:

Vogelmann, A., Schiedel, M., Woessner, N., Merz, A., Herp, D., Hammelmann, S.,... Jung, M. (2022). Development of a NanoBRET assay to validate inhibitors of Sirt2-mediated lysine deacetylation and defatty-acylation that block prostate cancer cell migration. RSC Chemical Biology. https://doi.org/10.1039/d1cb00244a

MLA:

Vogelmann, A., et al. "Development of a NanoBRET assay to validate inhibitors of Sirt2-mediated lysine deacetylation and defatty-acylation that block prostate cancer cell migration." RSC Chemical Biology (2022).

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