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Crystal structure of Sirt2 in complex with selective inhibitor L5C
Structural highlights
FunctionSIR2_HUMAN NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and non-histone proteins. Deacetylates 'Lys-40' of alpha-tubulin. Involved in the control of mitotic exit in the cell cycle, probably via its role in the regulation of cytoskeleton. Deacetylates PCK1, opposing proteasomal degradation. Deacetylates 'Lys-310' of RELA.[1] [2] [3] [4] Publication Abstract from PubMedHuman sirtuin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD(+))-dependent deacylase, and is implicated in human diseases including cancer. Selective small-molecule inhibitors for SIRT2 are sought as chemical tools and potential therapeutics. Here we report the X-ray crystal structure guided structure-activity relationship studies of new N-(3-(phenoxymethyl)phenyl)acetamide derivatives with SIRT2, which led to the identification of potent, selective SIRT2 inhibitors. Crystallographic analyses reveal that the new inhibitors act via inducing the formation of an enlarged hydrophobic pocket and particularly mimicking the interactions made by myristoylated-lysine substrates. The most potent inhibitor 24a could dose-dependently elevate the acetylation level of alpha-tubulin in the non-small cell lung cancer H441cells, which have a high expression level of SIRT2 as determinated by Western blotting analyses. Further cellular assays reveal that 24a restrains cell growth mainly through inhibiting cellular proliferation rather than inducing apoptosis. Moreover, 24a could suppress the migration and invasion of H441cells. These results provide an excellent basis for further development of new potent, selective, and cell active SIRT2 inhibitors as chemical tools and potential therapeutics for SIRT2-driven non-small cell lung cancers. X-ray crystal structure guided discovery of new selective, substrate-mimicking sirtuin 2 inhibitors that exhibit activities against non-small cell lung cancer cells.,Yang LL, Wang HL, Zhong L, Yuan C, Liu SY, Yu ZJ, Liu S, Yan YH, Wu C, Wang Y, Wang Z, Yu Y, Chen Q, Li GB Eur J Med Chem. 2018 Jul 15;155:806-823. doi: 10.1016/j.ejmech.2018.06.041. Epub , 2018 Jun 19. PMID:29957526[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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