Target Information

Target General Infomation
Target ID
T40111
Former ID
TTDS00062
Target Name
Inosine-5'-monophosphate dehydrogenase
Synonyms
IMP dehydrogenase; IMPD; IMPDH; Inosine dehydrogenase; NAD-dependent inosine monophosphate dehydrogenase; Probable inosine-5'-monophosphate dehydrogenase IMD1; SOI12; Superoxide-inducible protein 12
Target Type
Successful
Disease Acute lymphoblastic leukemia [ICD9: 204.0, 556; ICD10: C91.0]
Cancer [ICD9: 140-229; ICD10: C00-C96]
HCV infection [ICD9: 070.4, 070.5, 070.70; ICD10: B17.1, B18.2]
Hyperuricemia; Transplant rejection [ICD9:790.6, 279.5, 996; ICD10: E79.0, D89.8, T86]
Hepatitis virus infection [ICD9: 573.3; ICD10: K75.9]
Psoriasis [ICD9: 696; ICD10: L40]
Function
Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate- limiting step in the de novo synthesis of guaninenucleotides, and therefore plays an important role in the regulation of cell growth. Essential for mouse infection by tick bite and critical for the survival in environments that appear to lack sufficient amounts of guanine, guanosine, and/or deoxyguanosine to support spirochete growth, such as mammalian host tissues.
BioChemical Class
Short-chain dehydrogenases reductases
Target Validation
T40111
EC Number
EC 1.1.1.205
Drugs and Mode of Action
Drug(s) Mercaptopurine Drug Info Approved Acute lymphoblastic leukemia [1], [2]
Mizoribine Drug Info Approved Hyperuricemia; Transplant rejection [3], [4]
Ribavirin Drug Info Approved HCV infection [5], [6]
Tiazofurin Drug Info Approved Cancer [7]
Viramidine Drug Info Phase 3 HCV infection [8]
VX-148 Drug Info Discontinued in Phase 2 Psoriasis [9]
VX-497 Drug Info Discontinued in Phase 2 Hepatitis virus infection [10]
Inhibitor 6-Cl-IMP Drug Info [11]
Imidazo[4,5-e][1,4]diazapine nucleotide (I) Drug Info [12]
Inosinic Acid Drug Info [13]
Mercaptopurine Drug Info [14]
Mizoribine Drug Info [15], [16]
Ribavirin Drug Info [17], [18]
Selenazofurin Drug Info [19]
TAD Drug Info [20]
Tiazofurin Drug Info [21], [22], [19]
Viramidine Drug Info [23]
VX-148 Drug Info [24]
VX-497 Drug Info [15]
References
REF 1S-adenosylmethionine regulates thiopurine methyltransferase activity and decreases 6-mercaptopurine cytotoxicity in MOLT lymphoblasts. Biochem Pharmacol. 2009 Jun 15;77(12):1845-53. Epub 2009 Mar 19.
REF 2(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7226).
REF 3Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77. Epub 2007 Feb 20.
REF 4Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 5FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 076192.
REF 6(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6842).
REF 7De novo synthesis of two new cytotoxic tiazofurin analogues with modified sugar moieties. Bioorg Med Chem Lett. 2003 Oct 6;13(19):3167-70.
REF 8A phase III study of the safety and efficacy of viramidine versus ribavirin in treatment-na?ve patients with chronic hepatitis C: ViSER1 results. Hepatology. 2009 Sep;50(3):717-26.
REF 9Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800013965)
REF 10Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008158)
REF 11Identification of the IMP binding site in the IMP dehydrogenase from Tritrichomonas foetus. Biochemistry. 1995 Oct 24;34(42):13889-94.
REF 12A potent "fat base" nucleotide inhibitor of IMP dehydrogenase. Biochemistry. 1998 Aug 25;37(34):11949-52.
REF 13How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
REF 14Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol. 2008 Aug;64(8):753-67. Epub 2008 May 28.
REF 15VX-497: a novel, selective IMPDH inhibitor and immunosuppressive agent. J Pharm Sci. 2001 May;90(5):625-37.
REF 16Cofactor mimics as selective inhibitors of NAD-dependent inosine monophosphate dehydrogenase (IMPDH)--the major therapeutic target. Curr Med Chem. 2004 Apr;11(7):887-900.
REF 17A randomized, double-blind, placebo-controlled dose-escalation trial of merimepodib (VX-497) and interferon-alpha in previously untreated patients with chronic hepatitis C. Antivir Ther. 2005;10(5):635-43.
REF 18Treating HCV with ribavirin analogues and ribavirin-like molecules. J Antimicrob Chemother. 2006 Jan;57(1):8-13. Epub 2005 Nov 17.
REF 19In vitro and in vivo antiproliferative activity of IPCAR, a new pyrazole nucleoside analog. Anticancer Res. 1998 Jul-Aug;18(4A):2623-30.
REF 20Crystal structure of a ternary complex of Tritrichomonas foetus inosine 5'-monophosphate dehydrogenase: NAD+ orients the active site loop for catalysis. Biochemistry. 2002 Nov 5;41(44):13309-17.
REF 21Relationships between the cytotoxicity of tiazofurin and its metabolism by cultured human lung cancer cells. J Clin Invest. 1985 Jan;75(1):175-82.
REF 22Sequential impact of tiazofurin and ribavirin on the enzymic program of the bone marrow. Cancer Res. 1993 Dec 15;53(24):5982-6.
REF 23Antiviral agents active against influenza A viruses. Nat Rev Drug Discov. 2006 Dec;5(12):1015-25.
REF 24Characterization of pharmacological efficacy of VX-148, a new, potent immunosuppressive inosine 5'-monophosphate dehydrogenase inhibitor. J Pharmacol Exp Ther. 2002 Sep;302(3):1272-7.

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