title: Development of novel thiazolopyrimidines as CDC25B phosphatase inhibitors.
abstract: The development of CDC25 phosphatase inhibitors is an interesting approach toward new antitumor agents, as CDC25 play key roles in cell-cycle regulation and are overexpressed in numerous cancers. We previously reported a novel compound belonging to the thiazolopyrimidine family that inhibits CDC25 activity with an IC(50) value of 13 microM and displays cytotoxic properties against HeLa cells. Structural modifications were subsequently conducted on this new pharmacophore which led to a library of 45 thiazolopyrimidines. Regarding the in vitro effects, 14 compounds inhibit CDC25B with IC(50)<20 microM, with the most efficient inhibitor 44 improving the potency to 4.5 microM. Steady-state kinetics were performed and showed a mixed inhibition pattern for all tested compounds. Furthermore, 44 was able to revert the bypass of genotoxicity-induced G(2) arrest upon CDC25B overexpression, indicating that this compound targets the dual-specificity phosphatase in cultured cells. Finally, the cytotoxic activities of the compounds were determined against two human cancer cell lines. The results indicate that the prostatic LNCaP cell line is more sensitive to these derivatives than the pancreatic adenocarcinoma MiaPaCa-2 line. With its interesting enzymatic and cellular properties, compound 44 appears to be a promising CDC25B inhibitor for further development.
authors.affiliation: Université Paris Descartes, UFR Biomédicale, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Kolb
authors.forename: Odile
authors.initials: O
authors.lastname: Mondésert
authors.forename: Mary-Lorène
authors.initials: ML
authors.lastname: Goddard
authors.forename: Denis
authors.initials: D
authors.lastname: Jullien
authors.forename: Bruno O
authors.initials: BO
authors.lastname: Villoutreix
authors.forename: Bernard
authors.initials: B
authors.lastname: Ducommun
authors.forename: Christiane
authors.initials: C
authors.lastname: Garbay
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Braud
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry*; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D020687:cdc25 Phosphatases