title: Multidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cells.
abstract: Loss of VHR phosphatase causes cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells. We recently reported that VHR is upregulated in several cervix cancer cell lines as well as in carcinomas of the uterine cervix. Here we report the development of multidentate small-molecule inhibitors of VHR that inhibit its enzymatic activity at nanomolar concentrations and exhibit antiproliferative effects on cervix cancer cells. Chemical library screening was used to identify hit compounds, which were further prioritized in profiling and kinetic experiments. SAR analysis was applied in the search for analogs with improved potency and selectivity, resulting in the discovery of novel inhibitors that are able to interact with both the phosphate-binding pocket and several distinct hydrophobic regions within VHR's active site. This multidentate binding mode was confirmed by X-ray crystallography. The inhibitors decreased the proliferation of cervix cancer cells, while growth of primary normal keratinocytes was not affected. These compounds may be a starting point to develop drugs for the treatment of cervical cancer.
authors.affiliation: Infectious and Inflammatory Disease Center and Cancer Center, Burnham Institute for Medical Research, La Jolla, California 92037, USA.
authors.forename: Shuangding
authors.initials: S
authors.lastname: Wu
authors.forename: Sofie
authors.initials: S
authors.lastname: Vossius
authors.forename: Souad
authors.initials: S
authors.lastname: Rahmouni
authors.forename: Ana V
authors.initials: AV
authors.lastname: Miletic
authors.forename: Torkel
authors.initials: T
authors.lastname: Vang
authors.forename: Jesus
authors.initials: J
authors.lastname: Vazquez-Rodriguez
authors.forename: Fabio
authors.initials: F
authors.lastname: Cerignoli
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Arimura
authors.forename: Scott
authors.initials: S
authors.lastname: Williams
authors.forename: Tikva
authors.initials: T
authors.lastname: Hayes
authors.forename: Michel
authors.initials: M
authors.lastname: Moutschen
authors.forename: Stefan
authors.initials: S
authors.lastname: Vasile
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
authors.forename: Tomas
authors.initials: T
authors.lastname: Mustelin
authors.forename: Lutz
authors.initials: L
authors.lastname: Tautz
mesh_terms: D000873:Anthracenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000880:Anthraquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D004354:Drug Screening Assays, Antitumor; D054640:Dual Specificity Phosphatase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D007700:Kinetics; D008958:Models, Molecular; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids; D053778:Thiazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification; D002583:Uterine Cervical Neoplasms
chemical_list: D000873:Anthracenes; D000880:Anthraquinones; D000970:Antineoplastic Agents; D011720:Pyrazoles; D013451:Sulfonic Acids; D053778:Thiazolidines; D054640:Dual Specificity Phosphatase 3