Investigation of Carboxylic Acid Isosteres and Prodrugs for Inhibition of the Human SIRT5 Lysine Deacylase Enzyme**
Research output: Contribution to journal › Journal article › Research › peer-review
Documents
- Fulltext
Final published version, 1.23 MB, PDF document
Sirtuin 5 (SIRT5) is a protein lysine deacylase enzyme that regulates diverse biology by hydrolyzing ϵ-N-carboxyacyllysine posttranslational modifications in the cell. Inhibition of SIRT5 has been linked to potential treatment of several cancers but potent compounds with activity in cells have been lacking. Here we developed mechanism-based inhibitors that incorporate isosteres of a carboxylic acid residue that is important for high-affinity binding to the enzyme active site. By masking of the tetrazole moiety of the most potent candidate from our initial SAR study, we achieved potent and cytoselective growth inhibition for the treatment of SIRT5-dependent leukemic cancer cell lines in culture. Thus, we provide an efficient, cellularly active small molecule that targets SIRT5, which can help elucidate its function and potential as a future drug target. This work shows that masked isosteres of carboxylic acids are viable chemical motifs for the development of inhibitors that target mitochondrial enzymes, which may have applications beyond the sirtuin field.
| Original language | English |
|---|---|
| Article number | e202115805 |
| Journal | Angewandte Chemie - International Edition |
| Volume | 61 |
| Issue number | 22 |
| Number of pages | 9 |
| ISSN | 1433-7851 |
| DOIs | |
| Publication status | Published - 2022 |
Bibliographical note
Funding Information:
We thank Dr. Carlos Yruela‐Moreno for helpful discussion regarding fitting of kinetic data. Dr. Mette I. Rosenbaum and Dr. Laura Cesa are acknowledged for establishing the CAPA assay platform and Professor Joshua Kritzer for providing the HaloTag‐expressing HeLa cell line. We gratefully acknowledge financial support from the Hørslev Foundation, the Carlsberg Foundation (2013‐01‐0333, CF15‐011, and CF18‐0442; C.A.O.), the Novo Nordisk Foundation (NF17OC0029464; C.A.O.), and the Independent Research Fund Denmark‐Medical Sciences (0134‐00435B; C.A.O.). This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant agreement number CoG‐725172 ; C.A.O.). “SIRFUNCT”
Funding Information:
We thank Dr. Carlos Moreno-Yruela for helpful discussion regarding fitting of kinetic data. Dr. Mette I. Rosenbaum and Dr. Laura Cesa are acknowledged for establishing the CAPA assay platform and Professor Joshua Kritzer for providing the HaloTag-expressing HeLa cell line. We gratefully acknowledge financial support from the Hørslev Foundation, the Carlsberg Foundation (2013-01-0333, CF15-011, and CF18-0442; C.A.O.), the Novo Nordisk Foundation (NF17OC0029464; C.A.O.), and the Independent Research Fund Denmark-Medical Sciences (0134-00435B; C.A.O.). This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant agreement number CoG-725172 “SIRFUNCT”; C.A.O.).
- Bioisosteres, Enzyme Inhibitors, Prodrugs, SIRT5, Sirtuins
Research areas
Number of downloads are based on statistics from Google Scholar and www.ku.dk
ID: 308041099