Discovery of Novel Thiazole-Based SIRT2 Inhibitors as Anticancer Agents: Molecular Modeling, Chemical Synthesis and Biological Assays.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Sirtuin 2*/antagonists & inhibitors ; Sirtuin 2*/chemistry ; Sirtuin 2*/metabolism ; Thiazoles*/chemistry ; Thiazoles*/pharmacology ; Thiazoles*/chemical synthesis ; Antineoplastic Agents*/pharmacology ; Antineoplastic Agents*/chemistry ; Antineoplastic Agents*/chemical synthesis ; Molecular Docking Simulation*; Humans ; Structure-Activity Relationship ; Drug Discovery ; Models, Molecular ; Ligands ; Cell Line, Tumor

The search and development of effective sirtuin small molecule inhibitors (SIRTIs) continues to draw great attention due to their wide range of pharmacological applications. Based on SIRTs' involvement in different biological pathways, their ligands were investigated for many diseases, such as cancer, neurodegenerative disorders, diabetes, cardiovascular diseases and autoimmune diseases. The elucidation of a substantial number of SIRT2-ligand complexes is steering the identification of novel and more selective modulators. Among them, SIRT2 in the presence of the SirReal2 analog series was the most studied. On this basis, we recently reported structure-based analyses leading to the discovery of thiazole-based compounds acting as SIRT2 inhibitors ( T1 , SIRT2 IC 50 = 17.3 µM). Herein, ligand-based approaches followed by molecular docking simulations allowed us to evaluate in silico a novel small series of thiazoles ( 3a - 3d and 5a , 5d ) as putative SIRT2 inhibitors. Results from the computational studies revealed comparable molecular interaction fields (MIFs) and docking positionings of most of these compounds with respect to reference SIRT2Is. Biochemical and biological assays validated this study and pointed to compound 5a (SIRT2 IC 50 = 9.0 µM) as the most interesting SIRT2I that was worthy of further development as an anticancer agent.

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671881 European Union's Horizon 2020 research and innovation program - Marie Skłodow-ska-Curie; FRA University of Genova

Keywords: SIRT2; biochemical assays; cancer; drug design; enzymatic assays; inhibitor; molecular docking; sirtuin

EC 3.5.1.- (Sirtuin 2)
0 (Thiazoles)
0 (Antineoplastic Agents)
EC 3.5.1.- (SIRT2 protein, human)
0 (Ligands)

Date Created: 20241026 Date Completed: 20241026 Latest Revision: 20241104

20241105

PMC11508362

10.3390/ijms252011084

39456864