TY - JOUR

T1 - Investigation of Carboxylic Acid Isosteres and Prodrugs for Inhibition of the Human SIRT5 Lysine Deacylase Enzyme**

AU - Rajabi, Nima

AU - Hansen, Tobias N.

AU - Nielsen, Alexander L.

AU - Nguyen, Huy T.

AU - Bæk, Michael

AU - Bolding, Julie E.

AU - Bahlke, Oskar

AU - Petersen, Sylvester E.G.

AU - Bartling, Christian R.O.

AU - Strømgaard, Kristian

AU - Olsen, Christian A.

N1 - 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.).

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - Bioisosteres

KW - Enzyme Inhibitors

KW - Prodrugs

KW - SIRT5

KW - Sirtuins

U2 - 10.1002/anie.202115805

DO - 10.1002/anie.202115805

M3 - Journal article

C2 - 35299278

AN - SCOPUS:85127469668

VL - 61

JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

SN - 1433-7851

IS - 22

M1 - e202115805

ER -