title: Discovery of New SIRT2 Inhibitors by Utilizing a Consensus Docking/Scoring Strategy and Structure-Activity Relationship Analysis.
abstract: SIRT2, which is a NAD+ (nicotinamide adenine dinucleotide) dependent deacetylase, has been demonstrated to play an important role in the occurrence and development of a variety of diseases such as cancer, ischemia-reperfusion, and neurodegenerative diseases. Small molecule inhibitors of SIRT2 are thought to be potential interfering agents for relevant diseases. Discovery of SIRT2 inhibitors has attracted much attention recently. In this investigation, we adopted a consensus docking/scoring strategy to screen for novel SIRT2 inhibitors. Structural optimization and structure-activity relationship (SAR) analysis were then carried out on highly potent compounds with new scaffolds, which led to the discovery of 2-((5-benzyl-5H-[1,2,4]triazino[5,6-b]indol-3-yl)thio)-N-(naphthalen-1-yl)acetamide (SR86). This compound showed good activity against SIRT2 with an IC50value of 1.3 μM. SR86 did not exhibit activity against SIRT1 and SIRT3, implying a good selectivity for SIRT2. In in vitro cellular assays, SR86 displayed very good antiviability activity against breast cancer cell line MCF-7. In Western blot assays, SR86 showed considerable activity in blocking the deacetylation of α-tubulin, which is a typical substrate of SIRT2. Collectively, because of the new scaffold structure and good selectivity of SR86, it could serve as a promising lead compound, hence deserving further studies.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy , Chengdu, Sichuan 610041, China.
authors.forename: Shenzhen
authors.initials: S
authors.lastname: Huang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu, Sichuan 610041, China.
authors.forename: Chunli
authors.initials: C
authors.lastname: Song
authors.affiliation: Department of Clinical Medicine, School of Medicine, Nankai University , Tianjin 300071, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu, Sichuan 610041, China.
authors.forename: Guo
authors.initials: G
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy , Chengdu, Sichuan 610041, China.
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy , Chengdu, Sichuan 610041, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy , Chengdu, Sichuan 610041, China.
authors.forename: Qizheng
authors.initials: Q
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy , Chengdu, Sichuan 610041, China.
authors.forename: Luyi
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Clinical Medicine, School of Medicine, Nankai University , Tianjin 300071, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy , Chengdu, Sichuan 610041, China.
authors.forename: Yiguo
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu, Sichuan 610041, China.
authors.forename: Linli
authors.initials: L
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy , Chengdu, Sichuan 610041, China.
authors.forename: Shengyong
authors.identifier: 0000-0001-5147-3746
authors.initials: S
authors.lastname: Yang
mesh_terms: D000107:Acetylation; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D056565:Sirtuin 2