Target Validation Information
TTD ID	T78198
Target Name	Purine nucleoside phosphorylase (PNP)
Type of Target	Clinical trial
Drug Potency against Target	BCX-3408	Drug Info	IC50 = 0.5 nM	[6]
		Drug Info	Ki = 200 nM	[5]
	(+/-)-5'-deoxy-4'-fluoro-5'-methylthio-DADMe-ImmH	Drug Info	Ki = 5.8 nM	[2]
	3-((2-Pyrrolidine-1-yl)-ethyl)uracil	Drug Info	Ki = 6000 nM	[4]
	5'-deoxy-4'-hydroxy-5'-methylthio-DADMe-ImmH	Drug Info	Ki = 7.9 nM	[2]
	5'-Methylthio-ImmH	Drug Info	Ki = 101 nM	[2]
	5'-methylthio-immucillin-H	Drug Info	Ki = 303 nM	[4]
	5'-phenylthio-ImmH	Drug Info	Ki = 160 nM	[2]
	8-AMINOGUANINE	Drug Info	Ki = 800 nM	[5]
	9-(5,5-Difluoro-5-Phosphonopentyl)Guanine	Drug Info	IC50 = 18.7 nM	[3]
	BCX-3408	Drug Info	Ki = 0.1 nM	[1]
Action against Disease Model	BCX-3408	Drug Info	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.	[6]
References
REF 1	Azetidine based transition state analogue inhibitors of N-ribosyl hydrolases and phosphorylases. J Med Chem. 2008 Feb 28;51(4):948-56.
REF 2	Immucillins in custom catalytic-site cavities. Bioorg Med Chem Lett. 2008 Nov 15;18(22):5900-3.
REF 3	Structural-based design and synthesis of novel 9-deazaguanine derivatives having a phosphate mimic as multi-substrate analogue inhibitors for mamma... Bioorg Med Chem. 2010 Mar 15;18(6):2275-2284.
REF 4	Exploring new inhibitors of Plasmodium falciparum purine nucleoside phosphorylase. Eur J Med Chem. 2010 Nov;45(11):5140-9.
REF 5	Nucleosides. 5. Synthesis of guanine and formycin B derivatives as potential inhibitors of purine nucleoside phosphorylase. J Med Chem. 1993 Apr 16;36(8):1024-31.
REF 6	Potent 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.

If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.