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: Grushenka H I Wolfgang, Riri Shibata, Jianying Wang, Adrian S Ray, Sylvia Wu, Edward Doerrfler, Hans Reiser, William A Lee, Gabriel Birkus, Neil D Christensen, Graciela Andrei, Robert Snoeck
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 53 Issue 7 Pg. 2777-84 (Jul 2009) ISSN: 1098-6596 [Electronic] United States
• PMID: 19398642 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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