spacer Crystal Structure of human SIRT3 with ELT inhibitor 3 [14-(4-{2-[(methylsulfonyl)amino]ethyl}piperidin-1-yl)thieno[3,2-d]pyrimidine-6-carboxamide]
Primary citation
Title Discovery of Thieno[3,2-d]pyrimidine-6-carboxamides as Potent Inhibitors of SIRT1, SIRT2, and SIRT3.
Authors Disch,; Evindar,; Chiu,; Blum,; Dai,; Jin,; Schuman,; Lind,; Belyanskaya,; Deng,; Coppo,; Aquilani,; Graybill,; Cuozzo,; Lavu,; Mao,; Vlasuk,; Perni,
Journal vol:56, pag:3666-3679 (2013), Identifiers: PubMed ID (23570514)search DOI (10.1021/jm400204k)
Abstract The sirtuins SIRT1, SIRT2 and SIRT3 are NAD(+) dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic and neurodegenerative disorders. Encoded Library Technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g. 11c: IC50 = 3.6, 2.7 and 4.0 nM for SIRT1, SIRT2 and SIRT3 respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogs 28 and 31. Crystallographic studies of 11c, 28 and 31 bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR. These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors which makes them valuable tools for sirtuin research.
MeSH terms
Other entries described in this publication 4jt8, 4jsr