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Forodesine

Forodesine  is the hydrochloride salt of the synthetic high-affinity transition-state analogue forodesine. Forodesine binds preferentially to and inhibits purine nucleotide phosphorylase (PNP), resulting in the accumulation of deoxyguanosine triphosphate and the subsequent inhibition of the enzyme ribonucleoside diphosphate reductase and DNA synthesis. This agent selectively causes apoptosis in stimulated or malignant T-lymphocytes. A transition state analogue is a substrate designed to mimic the properties or the geometry of the transition state of reaction. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Forodesine has been granted Orphan Drug status by the FDA for three indications: T-cell non-Hodgkin's lymphoma, including CTCL; CLL and related leukemias including T-cell prolymphocytic leukemia, adult T-cell leukemia, and hairy cell leukemia; and for treatment of B-ALL. The FDA has also granted “fast track” status to the development of forodesine for the treatment of relapsed or refractory T-cell leukemia, and Special Protocol Assessment (SPA) from the FDA for forodesine to conduct a pivotal clinical trial in CTCL with an oral formulation. Forodesine (INN; also known as Immucillin H) is a transition-state analog inhibitor of purine nucleoside phosphorylase under development for the treatment of relapsed B-cell chronic lymphocytic leukemia  Forodesine is being developed by BioCryst Pharmaceuticals as Fodosine. As of 2008[update], it is currently in phase II clinical trials.

Forodesine (INN; also known as Immucillin H) was originally discovered by Vern Schramm's laboratory at the Albert Einstein College of Medicine in New York and Industrial Research, Ltd in New Zealand. [source: http://en.wikipedia.org/wiki/Forodesine].

Recent news about forodesine research:

BIRMINGHAM, Ala.--(BUSINESS WIRE)--Sep 15, 2010 - BioCryst Pharmaceuticals, Inc. (NASDAQ: BCRX) today announced preliminary top-line results from its multinational, open-label, single-arm trial evaluating 200 mg once-daily oral forodesine in the treatment of relapsed or refractory cutaneous T-cell lymphoma (CTCL), as well as interim results from the Company's exploratory Phase 2 study to investigate the efficacy and safety of 200 mg twice-daily oral forodesine as monotherapy for chronic lymphocytic leukemia (CLL). “These data expand our understanding of the potential role for forodesine and other purine nucleoside phosphorylase inhibitors in the treatment of patients with hematological malignancies,” said Jon P. Stonehouse, President and Chief Executive Officer of BioCryst. “We believe PNP inhibition is a potentially interesting mechanism for combination with other therapies and for earlier lines of therapy, based on the clinical activity and tolerability of forodesine.”

The study's primary endpoint was objective response rate, defined as complete or partial cutaneous response that is sustained for at least 28 days, in patients with later stage (stage IIB, III and IVA) disease who had previously received at least three systemic therapies for their disease. Eleven of 101 (11% [95% confidence interval: 6-19%]) later stage patients enrolled achieved a partial cutaneous response, while no patients achieved a complete response. Of the remaining later stage patients, 56 (55%) had stable disease as their best response, 30 (30%) had progressive disease, with a median time to progression of 353 days, and four (4%) were not evaluable. The median number of prior systemic therapies was four (range 3-15) among patients with later stage disease. Oral forodesine was generally safe and well-tolerated in this study, and was administered daily for up to 839 days. [source: http://www.drugs.com/clinical_trials/biocryst-reports-results-two-forodesine-oncology-studies-10097.html].

Current developer:    BioCryst Pharmaceuticals Inc.

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37: Huang M, Wang Y, Gu J, Yang J, Noel K, Mitchell BS, Schramm VL, Graves LM. Determinants of sensitivity of human T-cell leukemia CCRF-CEM cells to immucillin-H. Leuk Res. 2008 Aug;32(8):1268-78. Epub 2008 Feb 14. PubMed PMID: 18279955; PubMed Central PMCID: PMC2494856.

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47: Mundt JM, Hah SS, Sumbad RA, Schramm V, Henderson PT. Incorporation of extracellular 8-oxodG into DNA and RNA requires purine nucleoside phosphorylase in MCF-7 cells. Nucleic Acids Res. 2008 Jan;36(1):228-36. Epub 2007 Nov 19. PubMed PMID: 18025045; PubMed Central PMCID: PMC2248762.

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52: Rinaldo-Matthis A, Wing C, Ghanem M, Deng H, Wu P, Gupta A, Tyler PC, Evans GB, Furneaux RH, Almo SC, Wang CC, Schramm VL. Inhibition and structure of Trichomonas vaginalis purine nucleoside phosphorylase with picomolar transition state analogues. Biochemistry. 2007 Jan 23;46(3):659-68. PubMed PMID: 17223688; PubMed Central PMCID: PMC2517847.

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95: Lewandowicz A, Shi W, Evans GB, Tyler PC, Furneaux RH, Basso LA, Santos DS, Almo SC, Schramm VL. Over-the-barrier transition state analogues and crystal structure with Mycobacterium tuberculosis purine nucleoside phosphorylase. Biochemistry. 2003 May 27;42(20):6057-66. PubMed PMID: 12755607.

96: Sauve AA, Cahill SM, Zech SG, Basso LA, Lewandowicz A, Santos DS, Grubmeyer C, Evans GB, Furneaux RH, Tyler PC, McDermott A, Girvin ME, Schramm VL. Ionic states of substrates and transition state analogues at the catalytic sites of N-ribosyltransferases. Biochemistry. 2003 May 20;42(19):5694-705. PubMed PMID: 12741826.

97: Kilpatrick JM, Morris PE, Serota DG Jr, Phillips D, Moore DR, Bennett JC, Babu YS. Intravenous and oral pharmacokinetic study of BCX-1777, a novel purine nucleoside phosphorylase transition-state inhibitor. In vivo effects on blood 2'-deoxyguanosine in primates. Int Immunopharmacol. 2003 Apr;3(4):541-8. PubMed PMID: 12689658.

98: Macchia M, Cervetto L, Demontis GC, Longoni B, Minutolo F, Orlandini E, Ortore G, Papi C, Sbrana A, Macchia B. New N-n-propyl-substituted 3-aryl- and 3-cyclohexylpiperidines as partial agonists at the D4 dopamine receptor. J Med Chem. 2003 Jan 2;46(1):161-8. PubMed PMID: 12502370.

99: Kicska GA, Tyler PC, Evans GB, Furneaux RH, Shi W, Fedorov A, Lewandowicz A, Cahill SM, Almo SC, Schramm VL. Atomic dissection of the hydrogen bond network for transition-state analogue binding to purine nucleoside phosphorylase. Biochemistry. 2002 Dec 10;41(49):14489-98. PubMed PMID: 12463747.

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101: Schramm VL. Development of transition state analogues of purine nucleoside phosphorylase as anti-T-cell agents. Biochim Biophys Acta. 2002 Jul 18;1587(2-3):107-17. Review. PubMed PMID: 12084452.

102: Kicska GA, Tyler PC, Evans GB, Furneaux RH, Kim K, Schramm VL. Transition state analogue inhibitors of purine nucleoside phosphorylase from Plasmodium falciparum. J Biol Chem. 2002 Feb 1;277(5):3219-25. Epub 2001 Nov 13. PubMed PMID: 11707439.

103: Kicska GA, Tyler PC, Evans GB, Furneaux RH, Schramm VL, Kim K. Purine-less death in Plasmodium falciparum induced by immucillin-H, a transition state analogue of purine nucleoside phosphorylase. J Biol Chem. 2002 Feb 1;277(5):3226-31. Epub 2001 Nov 12. PubMed PMID: 11706018.

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105: Basso LA, Santos DS, Shi W, Furneaux RH, Tyler PC, Schramm VL, Blanchard JS. Purine nucleoside phosphorylase from Mycobacterium tuberculosis. Analysis of inhibition by a transition-state analogue and dissection by parts. Biochemistry. 2001 Jul 27;40(28):8196-203. PubMed PMID: 11444965.

106: Bantia S, Miller PJ, Parker CD, Ananth SL, Horn LL, Kilpatrick JM, Morris PE, Hutchison TL, Montgomery JA, Sandhu JS. Purine nucleoside phosphorylase inhibitor BCX-1777 (Immucillin-H)--a novel potent and orally active immunosuppressive agent. Int Immunopharmacol. 2001 Jun;1(6):1199-210. PubMed PMID: 11407314.

107: Kicska GA, Long L, Hörig H, Fairchild C, Tyler PC, Furneaux RH, Schramm VL, Kaufman HL. Immucillin H, a powerful transition-state analog inhibitor of purine nucleoside phosphorylase, selectively inhibits human T lymphocytes. Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4593-8. Epub 2001 Apr 3. PubMed PMID: 11287638; PubMed Central PMCID: PMC31879.

108: Fedorov A, Shi W, Kicska G, Fedorov E, Tyler PC, Furneaux RH, Hanson JC, Gainsford GJ, Larese JZ, Schramm VL, Almo SC. Transition state structure of purine nucleoside phosphorylase and principles of atomic motion in enzymatic catalysis. Biochemistry. 2001 Jan 30;40(4):853-60. PubMed PMID: 11170405.

109: Wang F, Miles RW, Kicska G, Nieves E, Schramm VL, Angeletti RH. Immucillin-H binding to purine nucleoside phosphorylase reduces dynamic solvent exchange. Protein Sci. 2000 Sep;9(9):1660-8. PubMed PMID: 11045613; PubMed Central PMCID: PMC2144693.

110: Shi W, Li CM, Tyler PC, Furneaux RH, Cahill SM, Girvin ME, Grubmeyer C, Schramm VL, Almo SC. The 2.0 A structure of malarial purine phosphoribosyltransferase in complex with a transition-state analogue inhibitor. Biochemistry. 1999 Aug 3;38(31):9872-80. PubMed PMID: 10433693.

111: Li CM, Tyler PC, Furneaux RH, Kicska G, Xu Y, Grubmeyer C, Girvin ME, Schramm VL. Transition-state analogs as inhibitors of human and malarial hypoxanthine-guanine phosphoribosyltransferases. Nat Struct Biol. 1999 Jun;6(6):582-7. PubMed PMID: 10360365.

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