Mechanism-based inhibitors of SIRT2: structure–activity relationship, X-ray structures, target engagement, regulation of α-tubulin acetylation and inhibition of breast cancer cell migration

Nielsen, Alexander L.; Rajabi, Nima; Kudo, Norio; Lundø, Kathrine; Moreno–Yruela, Carlos; Bæk, Michael; Fontenas, Martin; Lucidi, Alessia; Madsen, Andreas Stahl; Yoshida, Minoru; Olsen, Christian A.

doi:10.1039/d0cb00036a

Cited by 43 publications

(49 citation statements)

References 98 publications

(118 reference statements)

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“…It was hypothesized that such inhibitors could be designed by incorporating a thiocarbonyl-containing lysine residue known to enable sirtuin inhibition. 3,29,40,41 Based on insight from previous structureactivity relationship (SAR) studies targeting SIRT2 and SIRT5, including selectivity profiling and co-crystal structures, 32,35 we positioned the thiocarbonyl-containing lysine residue as the N-terminal amino acid. With a preliminary series of compounds, we addressed the length of the mitochondria-targeting peptide combined with e-N-thioacetylated or e-N-thiomyristoylated N-terminal lysine residues (see Schemes S1 and S2 for syntheses, ESI †).…”

Section: Structure-activity Relationship Studymentioning

confidence: 99%

“…S2, ESI †). 32,35 Based on this series, we proceeded with the 3-phenylpropionyl group (c; Fig. 2) and the alkynecontaining group (a, Fig.…”

Section: Structure-activity Relationship Studymentioning

confidence: 99%

“…2 and Scheme S6, ESI †), which is amenable to incorporation of fluorophores or other tags using Cu(I)-catalyzed azide-alkyne Huisgen 3+2 cycloaddition ''click'' chemistry. 45,46 Inspired by previous studies of SIRT1-3 29,35,[47][48][49][50][51] and the structures of the active sites in SIRT1-3 (Fig. S3, ESI †), we next analyzed a number of thiocarbonyl binding motifs (1-10; Fig.…”

Section: Structure-activity Relationship Studymentioning

confidence: 99%

“…This mechanism has been utilized to develop so-called mechanism-based inhibitors, by the use of substrate-mimicking chemotypes that form stalled intermediates in the active site of the sirtuin. [28][29][30][31][32][33][34][35] Many mechanismbased inhibitors exhibit high potency and, in several cases, high selectivity toward specific sirtuin subtypes. However, due to the shared mechanism and similar substrate preferences between SIRT1-3, it has been difficult to target SIRT3 selectively.…”

Section: Introductionmentioning

confidence: 99%

“…Among several demonstrated examples of mitochondrial targeting of various payloads, 36 a particularly appealing approach for our strategy was the mitochondria-targeting peptides developed by Kelley and co-workers. [37][38][39] Based on recent investigations of mechanism-based peptide inhibitors of other sirtuins, 32,35 we hypothesized that mitochondria-targeting peptide tags could be elaborated into potent inhibitors of the SIRT3 that would exhibit selectivity in cells (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

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Mitochondria-targeted inhibitors of the human SIRT3 lysine deacetylase

et al. 2021

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Section: Structure-activity Relationship Studymentioning

confidence: 99%

“…S2, ESI †). 32,35 Based on this series, we proceeded with the 3-phenylpropionyl group (c; Fig. 2) and the alkynecontaining group (a, Fig.…”

Section: Structure-activity Relationship Studymentioning

confidence: 99%

Section: Structure-activity Relationship Studymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitochondria-targeted inhibitors of the human SIRT3 lysine deacetylase

et al. 2021

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

et al. 2022

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Sirtuin 5 (SIRT5) is a protein lysine deacylase enzyme that regulates diverse biology by hydrolyzing ɛ-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 highaffinity 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 SIRT5dependent 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.

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Substrates and Cyclic Peptide Inhibitors of the Oligonucleotide‐Activated Sirtuin 7**

Bolding,

Nielsen,

Jensen

et al. 2023

Angewandte Chemie

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The sirtuins are NAD+‐dependent lysine deacylases, comprising seven isoforms (SIRT1–7) in humans, which are involved in the regulation of a plethora of biological processes, including gene expression and metabolism. The sirtuins share a common hydrolytic mechanism but display preferences for different ε‐N‐acyllysine substrates. SIRT7 deacetylates targets in nuclei and nucleoli but remains one of the lesser studied of the seven isoforms; in part, due to a lack of chemical tools to specifically probe SIRT7 activity. Here we expressed SIRT7 and, using small‐angle X‐ray scattering, reveal SIRT7 to be a monomeric enzyme with low degree of globular flexibility in solution. We developed a fluorogenic assay for investigation of the substrate preferences of SIRT7 and to evaluate compounds that modulate its activity. We report several mechanism‐based SIRT7 inhibitors as well as de novo cyclic peptide inhibitors selected from mRNA‐display library screening that exhibit selectivity for SIRT7 over other sirtuin isoforms, stabilize SIRT7 in cells, and cause increase in the acetylation H3K18.

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Mechanism-based inhibitors of SIRT2: structure–activity relationship, X-ray structures, target engagement, regulation of α-tubulin acetylation and inhibition of breast cancer cell migration

Abstract: Sirtuin 2 (SIRT2) is a protein deacylase enzyme that removes acetyl groups and longer chain acyl groups from post-translationally modified lysine residues. Here, we developed small peptide-based inhibitors of its activity in living cells in culture.

Cited by 43 publications

References 98 publications

Mitochondria-targeted inhibitors of the human SIRT3 lysine deacetylase

Mitochondria-targeted inhibitors of the human SIRT3 lysine deacetylase

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

Substrates and Cyclic Peptide Inhibitors of the Oligonucleotide‐Activated Sirtuin 7**

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