Delving into the Latest Updates on SIRT2 inhibitors(University of Freiburg) with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Compound 16

Target

SIRT2

Action

inhibitors

Mechanism

SIRT2 inhibitors(NAD-dependent protein deacetylase sirtuin-2 inhibitors), Epigenetic drug

Therapeutic Areas

NeoplasmsUrogenital Diseases

Active Indication

Prostatic Cancer

Inactive Indication-

Originator Organization

University of Freiburg

Active Organization

University of Freiburg

Inactive Organization-

License Organization-

Drug Highest PhaseDiscovery

First Approval Date-

Regulation-

Oxygen therapy is helpful for patients with breathing difficulties; however, sustained supplementation with high-concentration oxygen can cause hyperoxic acute lung injury. Sirtuin 2 (SIRT2), a nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase, has been shown to be involved in pulmonary fibrosis, apoptosis, and inflammation. Here, we elucidated the role of SIRT2 in hyperoxic acute lung injury.

METHODS:

Wild-type (WT) mice and SIRT2-deficient (SIRT2^-/-) mice were exposed to room air or hyperoxia for 72 h. Thereafter, changes in hyperoxia-induced responses were evaluated in WT and SIRT2^-/- mice.

RESULTS:

SIRT2 expression was elevated in WT mice after hyperoxic exposure. We also observed that the levels of SIRT2 were higher in tracheal aspirates from newborns with bronchopulmonary dysplasia (BPD) than in those without BPD. Hyperoxia-induced inflammation and apoptosis were more considerably attenuated in SIRT2^-/- mice than in WT mice. We also observed an interaction between SIRT2 and forkhead box O3 (FOXO3), and that SIRT2 deficiency was associated with altered acetylation levels of FOXO3 and changes in the expression of its downstream targets. Further investigation of the therapeutic effect of SIRT2 showed that hyperoxic acute lung injury was alleviated when AGK2, a SIRT2 inhibitor, was administered.

CONCLUSION:

Taken together, SIRT2 plays a critical role in the pathogenesis of hyperoxic acute lung injury by regulating apoptotic signaling. These findings indicated that SIRT2 is potentially a novel therapeutic strategy for hyperoxic acute lung injury.

01 Dec 2025·Central nervous system agents in medicinal chemistry

Identification of Phytoconstituents from Natural Product Database as SIRT2 Inhibitors for Potential Role in Alzheimer’s Disease: An In-Silico Screening

Article

Author: Kumar, Anoop ; Datusalia, Ashok Kumar ; Kumar, Hitesh ; Khatik, Gopal L.

Aim::

We aimed to conduct in silico screening of the potential phytoconstituent from a natural product database to find SIRT2 inhibitors.

Background::

Alzheimer's disease (AD) is the most prevalent type of dementia, characterized by behavioral and mental symptoms as well as a progressive loss of cognitive ability. Since SIRT2 may be detrimental to neurological illnesses, it is a prime target for research into SIRT2 inhibitors.

Objective::

To identify the SIRT2 inhibitors and their role in AD.

Methods::

We have utilized NPAtlas database and screened using pharmacophore-based virtual screening, molecular docking, and simulation. The Natural Products Atlas provides unrestricted access to various natural products derived from bacteria and fungi, allowing researchers to investigate and visualize the extensive chemical diversity in the natural world.

Results::

From in silico screening data, we have found phytoconstituents that could function as SIRT2 inhibitors. Six phytoconstituents were identified using pharmacophore-based virtual screening. According to molecular docking, Kurasoin B outperformed the reference molecule regarding binding energy. Kurasoin B exhibited a binding affinity of -12.543 kcal/mol, whereas the binding affinity of the reference molecule was -12.089 kcal/mol. The Kurasoin B complex with SIRT2 was determined to be stable throughout the simulation by performing MD simulation, with an RMSD of 2.88 (Å), whereas the reference and free protein displayed RMSDs of 3.74 and 4.70 (Å), respectively.

Conclusion::

In silico studies and data analysis, suggest that Kurasoin B may be able to suppress the SIRT2 protein for managing AD.

03 Aug 2025·Future Medicinal Chemistry

Discovery of novel SIRT2 inhibitors with anti-NSCLC activity through multi-virtual screening and biological evaluation

Article

Author: Zhu, Lingyan ; Li, Chaoqun ; Wang, Kewu ; Sun, Guoping

AIM:

Identify novel SIRT2 inhibitors for treating non-small cell lung cancer (NSCLC).

MATERIALS AND METHODS:

A hierarchical virtual screening strategy (combining ligand- and receptor-based pharmacophore modeling with molecular docking) screened a 203,415-compound library. Identified candidates were tested for SIRT2 inhibition using a fluorogenic assay (AcIQF). Anti-tumor effects (proliferation, apoptosis, migration, invasion) were assessed in high-SIRT2-expressing H441 NSCLC cells. Target engagement was confirmed via Western blot (WB) analysis of SIRT2 substrate acetylation. In vivo efficacy was evaluated using H441 xenograft models in nude mice.

RESULTS AND CONCLUSION:

Screening yielded 20 candidate SIRT2 inhibitors. Compound 7 was the most potent inhibitor. Mechanistically, Compound 7 dose-dependently increased acetylation of α-tubulin (a key SIRT2 substrate) in H441 cells, confirming direct target modulation. Cellular assays demonstrated that Compound 7 significantly inhibited H441 cell proliferation, induced apoptosis, and suppressed migration and invasion. Critically, Compound 7 also markedly inhibited tumor growth in H441 xenograft mouse models. These integrated results, spanning virtual screening to in vivo validation, identify Compound 7 as a promising lead compound. The study establishes a solid foundation for developing novel SIRT2 inhibitors as both chemical probes and potential therapeutics for SIRT2-driven NSCLC.

100 Deals associated with SIRT2 inhibitors(University of Freiburg)

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