New ε-N-thioglutaryl-lysine derivatives as SIRT5 inhibitors: Chemical synthesis, kinetic and crystallographic studies

• Published in: Bioorganic chemistry 2023-06, Vol.135, p.106487-106487, Article 106487
• Main Authors: Deng, Ji, Liu, Ze-Min, Zhu, Kai-Rong, Cui, Gui-Ling, Liu, Lin-Xia, Yan, Yu-Hang, Ning, Xiang-Li, Yu, Zhu-Jun, Li, Guo-Bo, Qi, Qing-Rong
• Format: Article
• Language: English
• Subjects: Binding Sites; Crystal Structure; Deacylase; Diazirine; Humans; Lysine - chemistry; SIRT5; Sirtuin; Sirtuins - metabolism
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106487

[Display omitted] •New ε-N-thioglutaryllysine derivatives displayed potent SIRT5 inhibition.•Derivative 8 manifested most selective and potent inhibition with an IC50 of 120 nM to SIRT5.•8 is likely to react with NAD+ and form stable thio-intermediates. SIRT5 has been implicated in various physiological processes and human diseases, including cancer. Development of new highly potent, selective SIRT5 inhibitors is still needed to investigate disease-related mechanisms and therapeutic potentials. We here report new ε-N-thioglutaryllysine derivatives, which were designed according to SIRT5-catalysed deacylation reactions. These ε-N-thioglutaryllysine derivatives displayed potent SIRT5 inhibition, of which the potential photo-crosslinking derivative 8 manifested most potent inhibition with an IC50 value of 120 nM to SIRT5, and low inhibition to SIRT1-3 and SIRT6. The enzyme kinetic assays revealed that the ε-N-thioglutaryllysine derivatives inhibit SIRT5 by lysine-substrate competitive manner. Co-crystallographic analyses demonstrated that 8 binds to occupy the lysine-substate binding site by making hydrogen-bonding and electrostatic interactions with SIRT5-specific residues, and is likely positioned to react with NAD+ and form stable thio-intermediates. Compound 8 was observed to have low photo-crosslinking probability to SIRT5, possibly due to inappropriate position of the diazirine group as observed in SIRT5:8 crystal structure. This study provides useful information for developing drug-like inhibitors and cross-linking chemical probes for SIRT5-related studies.