title: Identification and characterization of a new chemotype of noncovalent SENP inhibitors.
abstract: Enzymes called SENPs catalyze both the maturation of small ubiquitin-like modifier (SUMO) precursors and removal of SUMO modifications, which regulate essential cellular functions such as cell cycle progression, DNA damage response, and intracellular trafficking. Some members, such as SENP1, are potential targets for developing cancer therapeutics. We searched for small molecule inhibitors of SENPs using in silico screening in conjunction with biochemical assays and identified a new chemotype of small molecule inhibitors that noncovalently inhibit SENPs. The inhibitors confer the noncompetitive inhibitory mechanism, as shown by nuclear magnetic resonance (NMR) and quantitative enzyme kinetic analysis. The NMR data also provided evidence for substrate-assisted inhibitor binding, which indicates the need for caution in using artificial substrates for compound screening, as the inhibitory effects could be significantly different from using the physiological substrates. This finding also suggests the possibility of designing inhibitors for this class of enzymes that are tuned for substrate-specificity.
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute of the City of Hope , 1500 East Duarte Road, Duarte, California 91010, United States.
authors.forename: Ikenna G
authors.initials: IG
authors.lastname: Madu
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Namanja
authors.forename: Yang
authors.initials: Y
authors.lastname: Su
authors.forename: Steven
authors.initials: S
authors.lastname: Wong
authors.forename: Yi-Jia
authors.initials: YJ
authors.lastname: Li
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
mesh_terms: D020134:Catalytic Domain; D003546:Cysteine Endopeptidases; D004591:Electrophoresis, Polyacrylamide Gel; D010450:Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases