title: GS-9191 is a novel topical prodrug of the nucleotide analog 9-(2-phosphonylmethoxyethyl)guanine with antiproliferative activity and possible utility in the treatment of human papillomavirus lesions.
abstract: GS-9191 is a novel double prodrug of the nucleotide analog 9-(2-phosphonylmethoxyethyl)guanine (PMEG) designed as a topical agent to permeate skin and be metabolized to the active nucleoside triphosphate analog in the epithelial layer. The prodrug was shown to be metabolized intracellularly to 9-(2-phosphonylmethoxyethyl)-N(6)-cyclopropyl-2,6,diaminopurine (cPrPMEDAP) and subsequently deaminated to PMEG. The active form, PMEG diphosphate, was shown to be a potent inhibitor of DNA polymerase alpha and beta while showing weaker activity against mitochondrial DNA polymerase gamma (50% enzyme inhibition observed at 2.5, 1.6, and 59.4 microM, respectively). GS-9191 was markedly more potent than PMEG or cPrPMEDAP in a series of human papillomavirus (HPV)-positive cell lines, with effective concentrations to inhibit 50% cell growth (EC(50)) as low as 0.03, 207, and 284 nM, respectively. In contrast, GS-9191 was generally less potent in non-HPV-infected cells and primary cells (EC(50)s between 1 and 15 nM). DNA synthesis was inhibited by GS-9191 within 24 h of treatment; cells were observed to be arrested in S phase by 48 h and to subsequently undergo apoptosis (between 3 and 7 days). In an animal model (cottontail rabbit papillomavirus), topical GS-9191 was shown to decrease the size of papillomas in a dose-related manner. At the highest dose (0.1%), cures were evident at the end of 5 weeks, and lesions did not recur in a 30-day follow-up period. These data suggest that GS-9191 may have utility in the treatment of HPV-induced lesions.
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA, USA. gwolfgang@gilead.com
authors.forename: Grushenka H I
authors.initials: GH
authors.lastname: Wolfgang
authors.forename: Riri
authors.initials: R
authors.lastname: Shibata
authors.forename: Jianying
authors.initials: J
authors.lastname: Wang
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Ray
authors.forename: Sylvia
authors.initials: S
authors.lastname: Wu
authors.forename: Edward
authors.initials: E
authors.lastname: Doerrfler
authors.forename: Hans
authors.initials: H
authors.lastname: Reiser
authors.forename: William A
authors.initials: WA
authors.lastname: Lee
authors.forename: Gabriel
authors.initials: G
authors.lastname: Birkus
authors.forename: Neil D
authors.initials: ND
authors.lastname: Christensen
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D019384:Nucleic Acid Synthesis Inhibitors; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011355:Prodrugs / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; C543852:GS-9191; D019384:Nucleic Acid Synthesis Inhibitors; D011355:Prodrugs; D010649:Phenylalanine; D006147:Guanine