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

Antimicrob Agents Chemother. 2009 Jul;53(7):2777-84. doi: 10.1128/AAC.00103-09. Epub 2009 Apr 27.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • Cell Cycle / drug effects
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Female
  • Guanine / analogs & derivatives*
  • Guanine / pharmacology*
  • Guanine / therapeutic use
  • Humans
  • Male
  • Nucleic Acid Synthesis Inhibitors
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / pharmacology
  • Phenylalanine / therapeutic use
  • Prodrugs / pharmacology*
  • Prodrugs / therapeutic use
  • Rabbits
  • Uterine Cervical Neoplasms / drug therapy

Substances

  • Antineoplastic Agents
  • Antiviral Agents
  • GS-9191
  • Nucleic Acid Synthesis Inhibitors
  • Prodrugs
  • Phenylalanine
  • Guanine