Synthesis and biological evaluation of 9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile analogues as potential inhibitors of deubiquitinating enzymes.
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.
Colombo
Matteo
M
NiKem Research, via Zambeletti 25, 20021 Baranzate, Milan, Italy. matteo.colombo@nikemresearch.com
Vallese
Stefania
S
Peretto
Ilaria
I
Jacq
Xavier
X
Rain
Jean-Christophe
JC
Colland
Frédéric
F
Guedat
Philippe
P
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
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