title: Synthesis and biological evaluation of 9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile analogues as potential inhibitors of deubiquitinating enzymes.
abstract: High-throughput screening highlighted 9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (1) as an active inhibitor of ubiquitin-specific proteases (USPs), a family of hydrolytic enzymes involved in the removal of ubiquitin from protein substrates. The chemical behavior of compound 1 was examined. Moreover, the synthesis and in vitro evaluation of new compounds, analogues of 1, led to the identification of potent and selective inhibitors of the deubiquitinating enzyme USP8.
authors.affiliation: NiKem Research, via Zambeletti 25, 20021 Baranzate, Milan, Italy. matteo.colombo@nikemresearch.com
authors.forename: Matteo
authors.initials: M
authors.lastname: Colombo
authors.forename: Stefania
authors.initials: S
authors.lastname: Vallese
authors.forename: Ilaria
authors.initials: I
authors.lastname: Peretto
authors.forename: Xavier
authors.initials: X
authors.lastname: Jacq
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Rain
authors.forename: Frédéric
authors.initials: F
authors.lastname: Colland
authors.forename: Philippe
authors.initials: P
authors.lastname: Guedat
mesh_terms: D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D010450:Endopeptidases / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006801:Humans; D007192:Indenes / Q000737:chemistry* / Q000494:pharmacology; D008968:Molecular Conformation; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000076084:Ubiquitin-Specific Peptidase 7
chemical_list: C550627:9-oxo-9H-indeno(1,2-b)pyrazine-2,3-dicarbonitrile; D056827:Endosomal Sorting Complexes Required for Transport; D004791:Enzyme Inhibitors; D007192:Indenes; D011719:Pyrazines; D010450:Endopeptidases; C464569:USP7 protein, human; C541534:USP8 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7