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GS-9219

GS 9219 is a prodrug of the acyclic nucleoside phosphonate analogue 9-(2-phosphonylmethoxyethyl)guanine (PMEG) with potential antineoplastic activity. Formulated to selectively accumulate in lymphocytes, nucleotide analogue GS 9219 is converted to its active metabolite, PMEG diphosphate (PMEGpp), via enzymatic hydrolysis, deamination, and phosphorylation; subsequently, PMEGpp is incorporated into nascent DNA chains by DNA polymerases, which may result in the termination of DNA synthesis, S-phase cell cycle arrest, and the induction of apoptosis in susceptible lymphoma cell populations. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

GS-9219 was designed as a cytotoxic agent that preferentially targets lymphoid cells.  In lymphocytes, GS-9219 is converted to its active metabolite, PMEG diphosphate, via enzymic hydrolysis, deamination, and phosphorylation. GS-9219 has substantial antiproliferative activity against activated lymphocytes and hematopoietic tumor cell lines. In contrast, resting lymphocytes and solid tumor lines were less sensitive to GS-9219. GS-9219, but not PMEG, depleted the germinal centers in lymphoid tissues of normal beagle dogs at doses that were tolerated. In addn., GS-9219 displayed significant in vivo efficacy in five dogs with spontaneous NHL after a single administration, with either no or low-grade adverse events.  GS-9219 may have utility for the treatment of NHL.

Current developer:   

 1. Tsai, Cheng-Yu. The cellular and molecular responses to a novel nucleotide analogue, GS-9219. (2009), 180 pp. CAN 152:111115 AN 2009:1620128

2. Krecmerova, Marcela; Holy, Antonin. Syntheses of antiviral agents from the family of acyclic nucleoside phosphonates and their prodrugs. PharmaChem (2009), 8(6), 6-9. CODEN: PHARGZ ISSN:1720-4003. CAN 152:429917 AN 2009:1091799

3. Tsai, Cheng-Yu; Ray, Adrian S.; Tumas, Daniel B.; Keating, Michael J.; Reiser, Hans; Plunkett, William. Targeting DNA Repair in Chronic Lymphocytic Leukemia Cells with a Novel Acyclic Nucleotide Analogue, GS-9219. Clinical Cancer Research (2009), 15(11), 3760-3769. CODEN: CCREF4 ISSN:1078-0432. CAN 152:135829 AN 2009:657082

4. Vail, David M.; Thamm, Douglas H.; Reiser, Hans; Ray, Adrian S.; Wolfgang, Grushenka H. I.; Watkins, William J.; Babusis, Darius; Henne, Ilana N.; Hawkins, Michael J.; Kurzman, Ilene D.; Jeraj, Robert; Vanderhoek, Matt; Plaza, Susan; Anderson, Christie; Wessel, Mackenzie A.; Robat, Cecilia; Lawrence, Jessica; Tumas, Daniel B. Assessment of GS-9219 in a Pet Dog Model of Non-Hodgkin's Lymphoma. Clinical Cancer Research (2009), 15(10), 3503-3510. CODEN: CCREF4 ISSN:1078-0432. CAN 152:254416 AN 2009:606605

5. Otova, Berta; Hrdy, Jiri; Votruba, Ivan; Holy, Antonin. In vivo modulation of angiogenic gene expression by acyclic nucleoside phosphonates PMEDAP and PMEG. Anticancer Research (2009), 29(4), 1295-1302. CODEN: ANTRD4 ISSN:0250-7005. CAN 151:440017 AN 2009:514313

6. Cihlar, Tomas. Amidate prodrugs of nucleoside phosphonates: from design to in vivo proof of concept. Collection Symposium Series (2008), 10(Chemistry of Nucleic Acid Components), 45-53. CODEN: CSYSFN AN 2008:807512

7. Reiser, Hans; Wang, Jianying; Chong, Lee; Watkins, William J.; Ray, Adrian S.; Shibata, Riri; Birkus, Gabriel; Cihlar, Tomas; Wu, Sylvia; Li, Bei; Liu, Xiaohong; Henne, Ilana N.; Wolfgang, Grushenka H. I.; Desai, Manoj; Rhodes, Gerald R.; Fridland, Arnold; Lee, William A.; Plunkett, William; Vail, David; Thamm, Douglas H.; Jeraj, Robert; Tumas, Daniel B. GS-9219-A Novel Acyclic Nucleotide Analogue with Potent Antineoplastic Activity in Dogs with Spontaneous Non-Hodgkin's Lymphoma. Clinical Cancer Research (2008), 14(9), 2824-2832. CODEN: CCREF4 ISSN:1078-0432. AN 2008:550005

8. Schinkmanova, Marketa; Votruba, Ivan; Shibata, Riri; Han, Bin; Liu, Xiaohong; Cihlar, Tomas; Holy, Antonin. Human N6-methyl-AMP/DAMP aminohydrolase (abacavir 5'-monophosphate deaminase) is capable of metabolizing N6-substituted purine acyclic nucleoside phosphonates. Collection of Czechoslovak Chemical Communications (2008), 73(2), 275-291. CODEN: CCCCAK ISSN:0010-0765. CAN 149:238654 AN 2008:362343

9. Votruba I; Otova B; Holy A Acyclic nucleoside phosphonates as potential antineoplastic agents. Casopis lekar u c eskych (2008), 147(9), 471-7. Journal code: 0004743. ISSN:0008-7335. PubMed ID 18988489 AN 2008722468 MEDLINE (Copyright (C) 2010 U.S. National Library of Medicine on SciFinder (R))

10. Anonymous Preclinical data expected for nucleotide GS 9219. AIDS patient care and STDs (2007), 21(4), 289-90. Journal code: 9607225. ISSN:1087-2914. PubMed ID 17506142 AN 2007294594 MEDLINE (Copyright (C) 2010 U.S. National Library of Medicine on SciFinder (R))