SIRT2 inhibitors(University of Freiburg)

Selective and controlled expansion of endogenous β cells has been pursued as a potential therapy for diabetes. Ideally, such therapies would preserve feedback control of β cell proliferation to avoid excessive β cell expansion. Here, we identified a regulator of β cell proliferation whose inactivation resulted in controlled β cell expansion: the protein deacetylase sirtuin 2 (SIRT2). Sirt2 deletion in β cells of mice increased β cell proliferation during hyperglycemia with little effect under homeostatic conditions, indicating preservation of feedback control of β cell mass. SIRT2 restrains proliferation of human islet β cells, demonstrating conserved SIRT2 function. Analysis of acetylated proteins in islets treated with a SIRT2 inhibitor revealed that SIRT2 deacetylates enzymes involved in oxidative phosphorylation, dampening the adaptive increase in oxygen consumption during hyperglycemia. At the transcriptomic level, Sirt2 inactivation has context-dependent effects on β cells, with Sirt2 controlling how β cells interpret hyperglycemia as a stress. Finally, we provide proof of principle that systemic administration of a glucagon-like peptide 1-coupled (GLP1-coupled), Sirt2-targeting antisense oligonucleotide achieves β cell Sirt2 inactivation and stimulates β cell proliferation during hyperglycemia. Overall, these studies identify a therapeutic strategy for increasing β cell mass in diabetes without circumventing feedback control of β cell proliferation. Future work should test the extent to which these findings translate to human β cells from individuals with or without diabetes.

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

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.

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.