Project Details
Projekt
Sirtuin-2 (Sirt2) ligands as inhibitors of lysine long-chain deacylation and chemical tools for protein degradation
Subject Area
Pharmacy
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 503267011
Sirtuins are NAD-dependent lysine deacylases that cleave off acetyl but also long chain acyl groups from lysines in histones and other substrate proteins. This posttranslational modification is regulating key cellular processes like metabolism, cell proliferation and migration. The Sirtuin isotype Sirtuin2 (Sirt2) has been postulated as a target for the development for drugs in oncology, inflammation and neurodegeneration. A dual inhibition of deacetylation and long chain deacylation has been postulated as highly effecive for potential anticancer drugs. In previous work we have developed new lead structures for potent and selective Sirt2 inhibitors that have this dual inhibition profile and block cancer cell migration better than selective acetylation inhibitors. In addition, we have discovered selective inhibitors for long chain deacylation which are unprecedented so far. In this project, we want to optimize potency and cellular efficacy of dual acetylation/deacylation and selective deacylation inhibitors to further dissect the role of the different amidohydrolase activities of Sirt2 and to exploit their therapeutic potential. Besides „classical“, occupancy based inhibitors we also aim at developing new Proteolysis targeting chimeras (PROTACs) for Sirt2 as an orthogonal apporach. that are hybrid inhibitors which simultaneously engage Sirt2 and a suitable E3 ligase. This leads to Sirt2 ubiquitylation and subsequent proteasomal degradation and will also result in a dual activity profile. Besides validated ligases like Cereblon and VHL we will develop new ligands for the ligase Parkin which we had discovered to be suitable for Sirt2 degradation and will expand the available arsenal for Sirt2 PROTACs and PROTACs in general.
DFG Programme
Research Grants
International Connection
Netherlands, USA
Cooperation Partners
Dr. Stephan Hacker; Professor Dr. Hening Lin
