title: IRC-083864, a novel bis quinone inhibitor of CDC25 phosphatases active against human cancer cells.
abstract: CDC25 phosphatases are key actors in cyclin-dependent kinases activation whose role is essential at various stages of the cell cycle. CDC25 expression is upregulated in a number of human cancers. CDC25 phosphatases are therefore thought to represent promising novel targets in cancer therapy. Here, we report the identification and the characterization of IRC-083864, an original bis-quinone moiety that is a potent and selective inhibitor of CDC25 phosphatases in the low nanomolar range. IRC-083864 inhibits cell proliferation of a number of cell lines, regardless of their resistance to other drugs. It irreversibly inhibits cell proliferation and cell cycle progression and prevents entry into mitosis. In addition, it inhibits the growth of HCT-116 tumor spheroids with induction of p21 and apoptosis. Finally, IRC-083864 reduced tumor growth in mice with established human prostatic and pancreatic tumor xenografts. This study describes a novel compound, which merits further study as a potential anticancer agent.
authors.affiliation: IPSEN, Institut Henri Beaufour, 5 Avenue du Canada, Les Ulis, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Brezak
authors.forename: Annie
authors.initials: A
authors.lastname: Valette
authors.forename: Muriel
authors.initials: M
authors.lastname: Quaranta
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Contour-Galcera
authors.forename: Denis
authors.initials: D
authors.lastname: Jullien
authors.forename: Olivier
authors.initials: O
authors.lastname: Lavergne
authors.forename: Céline
authors.initials: C
authors.lastname: Frongia
authors.forename: Dennis
authors.initials: D
authors.lastname: Bigg
authors.forename: Philip G
authors.initials: PG
authors.lastname: Kasprzyk
authors.forename: Grégoire Pierre
authors.initials: GP
authors.lastname: Prevost
authors.forename: Bernard
authors.initials: B
authors.lastname: Ducommun
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000627:therapeutic use*; D001583:Benzoxazoles / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011809:Quinones / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors*
chemical_list: C535248:2-(2,5-difluorophenyl)-6-((3-(methyl(3-((2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino)propyl)amino)propyl)amino)-1,3-benzoxazole-4,7-dione; D052160:Benzothiazoles; D001583:Benzoxazoles; D004791:Enzyme Inhibitors; D011809:Quinones; D018844:Cyclin-Dependent Kinases; D020687:cdc25 Phosphatases