Target Validation Information
Target ID T78198
Target Name Purine nucleoside phosphorylase
Target Type
Clinical Trial
Drug Potency against Target BCX-4208 Drug Info IC50 = 0.5 nM [553042]
3-((2-Pyrrolidine-1-yl)-ethyl)uracil Drug Info Ki = 6000 nM [531149]
8-AMINOGUANINE Drug Info Ki = 800 nM [534048]
5'-deoxy-4'-hydroxy-5'-methylthio-DADMe-ImmH Drug Info Ki = 7.9 nM [529677]
5'-Methylthio-ImmH Drug Info Ki = 101 nM [529677]
(+/-)-5'-deoxy-4'-fluoro-5'-methylthio-DADMe-ImmH Drug Info Ki = 5.8 nM [529677]
BCX-3408 Drug Info Ki = 0.1 nM [529290]
9-(5',5'-difluoro-5'-phosphonopentyl)guanine Drug Info IC50 = 18.7 nM [530755]
5'-methylthio-immucillin-H Drug Info Ki = 303 nM [531149]
2,8-Diamino-9-benzyl-1,9-dihydro-purin-6-one Drug Info Ki = 200 nM [534048]
5'-phenylthio-ImmH Drug Info Ki = 160 nM [529677]
Action against Disease Model BCX-4208 BCX-4208 is a novel potent transition state analog inhibitor of h uMan PNP with an IC(50) of 0.5 nM. PNP inhibition leads to elevation of dGuo which is converted to dGTP mainly in lymphocytes causing imbalance in deoxynucleotide (dNTP) pools and cell apoptosis. In in vitro studies, neither BCX-4208 nor dGuo alone inhibits proliferation of lymphocytes. BCX-4208 in the presence of 10 microM deoxyguanosine (dGuo) inhibits lymphocyte proliferation induced by MLR, IL-2 or Con A with IC(50)s of 0.159, 0.26 and 0.73 microM, respectively. The IC(50) for dGuo in the presence of 1microM BCX-4208 for the IL-2 stimulated lymphocytes was 3.12 microM. dGTP in h uMan lymphocytes is elevated and a 3-5 fold increase in dGTP results in 50% inhibition after in vitro exposure to BCX-4208 and dGuo. Flow cytometric analyses of h uMan lymphocytes using annexin V staining reveal that BCX-4208 in the presence of dGuo induces cellular apoptosis in T-cells (CD3+), B-cells (CD20+, CD19+) and NK (CD56+) cells. BCX-4208 is orally bioavailable in mice and elevates plasma dGuo levels to 3.7 microM (predose levels<0.004 microM), similar to levels seen in PNP-deficient patients and levels needed to cause apoptosis in T and B-cells. These data support the evaluation of BCX-4208 in the treatment of T-cell and B-cell mediated diseases. [553042] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations We generated purine nucleoside phosphorylase (PNP)-deficient mice to gain insight into the mechanism of immune deficiency disease associated with PNP deficiency in h uMans. Similar to the h uMan disease, PNP deficiency in mice causes an immunodeficiency that affects T lymphocytes more severely than B lymphocytes. PNP knockout mice exhibit impaired thymocyte differentiation, reduced mitogenic and allogeneic responses, and decreased n uMbers of maturing thymocytes and peripheral T cells. T lymphocytes of PNP-deficient mice exhibit increased apoptosis in vivo and higher sensitivity to gamma irradiation in vitro. We propose that the immune deficiency in PNP deficiency is a result of inhibition of mitochondrial DNA repair due to the acc uMulation of dGTP in the mitochondria. The end result is increased sensitivity of T cells to spontaneous mitochondrial DNA damage, leading to T cell depletion by apoptosis [553042]
References
Ref 553042Potent orally bioavailable purine nucleoside phosphorylase inhibitor BCX-4208 induces apoptosis in B- and T-lymphocytes--a novel treatment approach for autoimmune diseases, organ transplantation and hematologic malignancies. Int Immunopharmacol. 2010 Jul;10(7):784-90. doi: 10.1016/j.intimp.2010.04.009. Epub 2010 Apr 22.
Ref 553042Potent orally bioavailable purine nucleoside phosphorylase inhibitor BCX-4208 induces apoptosis in B- and T-lymphocytes--a novel treatment approach for autoimmune diseases, organ transplantation and hematologic malignancies. Int Immunopharmacol. 2010 Jul;10(7):784-90. doi: 10.1016/j.intimp.2010.04.009. Epub 2010 Apr 22.
Ref 531149Eur J Med Chem. 2010 Nov;45(11):5140-9. Epub 2010 Aug 14.Exploring new inhibitors of Plasmodium falciparum purine nucleoside phosphorylase.
Ref 534048J Med Chem. 1993 Apr 16;36(8):1024-31.Nucleosides. 5. Synthesis of guanine and formycin B derivatives as potential inhibitors of purine nucleoside phosphorylase.
Ref 529677Bioorg Med Chem Lett. 2008 Nov 15;18(22):5900-3. Epub 2008 Aug 19.Immucillins in custom catalytic-site cavities.
Ref 529677Bioorg Med Chem Lett. 2008 Nov 15;18(22):5900-3. Epub 2008 Aug 19.Immucillins in custom catalytic-site cavities.
Ref 529677Bioorg Med Chem Lett. 2008 Nov 15;18(22):5900-3. Epub 2008 Aug 19.Immucillins in custom catalytic-site cavities.
Ref 529290J Med Chem. 2008 Feb 28;51(4):948-56. Epub 2008 Feb 6.Azetidine based transition state analogue inhibitors of N-ribosyl hydrolases and phosphorylases.
Ref 530755Bioorg Med Chem. 2010 Mar 15;18(6):2275-84. Epub 2010 Feb 4.Structural-based design and synthesis of novel 9-deazaguanine derivatives having a phosphate mimic as multi-substrate analogue inhibitors for mammalian PNPs.
Ref 531149Eur J Med Chem. 2010 Nov;45(11):5140-9. Epub 2010 Aug 14.Exploring new inhibitors of Plasmodium falciparum purine nucleoside phosphorylase.
Ref 534048J Med Chem. 1993 Apr 16;36(8):1024-31.Nucleosides. 5. Synthesis of guanine and formycin B derivatives as potential inhibitors of purine nucleoside phosphorylase.
Ref 529677Bioorg Med Chem Lett. 2008 Nov 15;18(22):5900-3. Epub 2008 Aug 19.Immucillins in custom catalytic-site cavities.

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