Target Information

Target General Information

Target ID

T40111 (Former ID: TTDS00062)

Target Name

Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1)

Synonyms

Superoxide-inducible protein 12; SOI12; Probable inosine-5'-monophosphate dehydrogenase IMD1; NAD-dependent inosine monophosphate dehydrogenase; Inosine dehydrogenase; IMPDH-I; IMPDH 1; IMPDH; IMPD1; IMPD 1; IMPD; IMP dehydrogenase 1; IMP dehydrogenase

Gene Name

IMPDH1

Target Type

Successful target

[1]

Disease

[+] 5 Target-related Diseases

Breast cancer [ICD-11: 2C60-2C6Y]

Hepatitis virus infection [ICD-11: 1E50-1E51]

Mature B-cell lymphoma [ICD-11: 2A85]

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Transplant rejection [ICD-11: NE84]

Function

Could also have a single-stranded nucleic acid-binding activity and could play a role in RNA and/or DNA metabolism. It may also have a role in the development of malignancy and the growth progression of some tumors. 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 guanine nucleotides, and therefore plays an important role in the regulation of cell growth.

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BioChemical Class

CH-OH donor oxidoreductase

UniProt ID

IMDH1_HUMAN

EC Number

EC 1.1.1.205

Sequence

MADYLISGGTGYVPEDGLTAQQLFASADGLTYNDFLILPGFIDFIADEVDLTSALTRKIT
LKTPLISSPMDTVTEADMAIAMALMGGIGFIHHNCTPEFQANEVRKVKKFEQGFITDPVV
LSPSHTVGDVLEAKMRHGFSGIPITETGTMGSKLVGIVTSRDIDFLAEKDHTTLLSEVMT
PRIELVVAPAGVTLKEANEILQRSKKGKLPIVNDCDELVAIIARTDLKKNRDYPLASKDS
QKQLLCGAAVGTREDDKYRLDLLTQAGVDVIVLDSSQGNSVYQIAMVHYIKQKYPHLQVI
GGNVVTAAQAKNLIDAGVDGLRVGMGCGSICITQEVMACGRPQGTAVYKVAEYARRFGVP
IIADGGIQTVGHVVKALALGASTVMMGSLLAATTEAPGEYFFSDGVRLKKYRGMGSLDAM
EKSSSSQKRYFSEGDKVKIAQGVSGSIQDKGSIQKFVPYLIAGIQHGCQDIGARSLSVLR
SMMYSGELKFEKRTMSAQIEGGVHGLHSYEKRLY

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3D Structure

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PDB

HIT2.0 ID

T00RT4

Drugs and Modes of Action

Top

Approved Drug(s)

[+] 5 Approved Drugs

Mercaptopurine

Drug Info

Approved

Acute lymphoblastic leukaemia

[2], [3]

Merimepodib

Drug Info

Approved

Breast cancer

[4]

Mizoribine

Drug Info

Approved

Transplant rejection

[5], [6]

Ribavirin

Drug Info

Approved

Hepatitis C virus infection

[7], [8]

Tiazofurin

Drug Info

Approved

Solid tumour/cancer

[9]

Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

Viramidine

Drug Info

Phase 3

Hepatitis C virus infection

[10]

VX-944

Drug Info

Phase 2

Solid tumour/cancer

[11]

Patented Agent(s)

[+] 1 Patented Agents

VX-148

Drug Info

Patented

Psoriasis vulgaris

[12]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

Phenacetin

Drug Info

Withdrawn from market

Analgesia

[13], [14]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 69 Inhibitor drugs

Mercaptopurine

Drug Info

[1]

Merimepodib

Drug Info

[15], [16]

Mizoribine

Drug Info

[15], [17]

Ribavirin

Drug Info

[18], [19]

Tiazofurin

Drug Info

[20], [21], [22]

Viramidine

Drug Info

[23]

VX-944

Drug Info

[16]

Carbamide derivative 10

Drug Info

[16]

Carbamide derivative 11

Drug Info

[16]

Carbamide derivative 4

Drug Info

[16]

Carbamide derivative 5

Drug Info

[16]

Carbamide derivative 6

Drug Info

[16]

Carbamide derivative 7

Drug Info

[16]

Carbamide derivative 8

Drug Info

[16]

Carbamide derivative 9

Drug Info

[16]

Mycophenolic acid/nucleotide derivative 1

Drug Info

[16]

Mycophenolic acid/nucleotide derivative 10

Drug Info

[16]

Mycophenolic acid/nucleotide derivative 11

Drug Info

[16]

Mycophenolic acid/nucleotide derivative 12

Drug Info

[16]

Mycophenolic acid/nucleotide derivative 2

Drug Info

[16]

Mycophenolic acid/nucleotide derivative 3

Drug Info

[16]

Mycophenolic acid/nucleotide derivative 4

Drug Info

[16]

Mycophenolic acid/nucleotide derivative 5

Drug Info

[16]

Mycophenolic acid/nucleotide derivative 6

Drug Info

[16]

Mycophenolic acid/nucleotide derivative 7

Drug Info

[16]

Mycophenolic acid/nucleotide derivative 8

Drug Info

[16]

Mycophenolic acid/nucleotide derivative 9

Drug Info

[16]

PMID28074661-Compound-US20100022547C80

Drug Info

[16]

PMID28074661-Compound-US20100022547C81

Drug Info

[16]

PMID28074661-Compound-US20100022547C82

Drug Info

[16]

PMID28074661-Compound-US20100022547C83

Drug Info

[16]

PMID28074661-Compound-US20100022547C86

Drug Info

[16]

PMID28074661-Compound-US20100022547C87

Drug Info

[16]

PMID28074661-Compound-US20100022547C88

Drug Info

[16]

PMID28074661-Compound-US20120264760C80

Drug Info

[16]

PMID28074661-Compound-US20120264760C81

Drug Info

[16]

PMID28074661-Compound-US20120264760C82

Drug Info

[16]

PMID28074661-Compound-US20120264760C83

Drug Info

[16]

PMID28074661-Compound-US20120264760C86

Drug Info

[16]

PMID28074661-Compound-US20120264760C87

Drug Info

[16]

PMID28074661-Compound-US20120264760C88

Drug Info

[16]

PMID28074661-Compound-US20128202889C90

Drug Info

[16]

PMID28074661-Compound-US20158969342C84

Drug Info

[16]

PMID28074661-Compound-US20169447134C85

Drug Info

[16]

PMID28074661-Compound-WO2009018344C78

Drug Info

[16]

PMID28074661-Compound-WO2009018344C79

Drug Info

[16]

Quinazolinone derivative 1

Drug Info

[16]

Quinazolinone derivative 2

Drug Info

[16]

Quinolone derivative 1

Drug Info

[16]

Urea and carbamate bioisostere derivative 10

Drug Info

[16]

Urea and carbamate bioisostere derivative 11

Drug Info

[16]

Urea and carbamate bioisostere derivative 13

Drug Info

[16]

Urea and carbamate bioisostere derivative 14

Drug Info

[16]

Urea and carbamate bioisostere derivative 15

Drug Info

[16]

Urea and carbamate bioisostere derivative 16

Drug Info

[16]

Urea and carbamate bioisostere derivative 18

Drug Info

[16]

Urea and carbamate bioisostere derivative 2

Drug Info

[16]

Urea and carbamate bioisostere derivative 3

Drug Info

[16]

Urea and carbamate bioisostere derivative 4

Drug Info

[16]

Urea and carbamate bioisostere derivative 5

Drug Info

[16]

Urea and carbamate bioisostere derivative 6

Drug Info

[16]

Urea and carbamate bioisostere derivative 7

Drug Info

[16]

Urea and carbamate bioisostere derivative 9

Drug Info

[16]

VX-148

Drug Info

[24], [16]

Phenacetin

Drug Info

[25]

6-Cl-IMP

Drug Info

[26]

Inosinic Acid

Drug Info

[27]

Selenazofurin

Drug Info

[20]

TAD

Drug Info

[28]

Chemical Structure based Activity Landscape of Target

Top

Drug Property Profile of Target

Top

(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

Top

Co-Targets

Co-Targets Info

Target Poor or Non Binders

Top

Target Poor or Non Binders

Target Poor or Non Binders Info

Target-Related Models and Studies

Top

Target Validation

Target Validation Info

References

Top

REF 1

Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol. 2008 Aug;64(8):753-67.

REF 2

URL: 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 3

S-adenosylmethionine regulates thiopurine methyltransferase activity and decreases 6-mercaptopurine cytotoxicity in MOLT lymphoblasts. Biochem Pharmacol. 2009 Jun 15;77(12):1845-53.

REF 4

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 022059.

REF 5

Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.

REF 6

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 7

REF 8

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 076192.

REF 9

De novo synthesis of two new cytotoxic tiazofurin analogues with modified sugar moieties. Bioorg Med Chem Lett. 2003 Oct 6;13(19):3167-70.

REF 10

A 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 11

ClinicalTrials.gov (NCT00493441) AVN944 in Combination With Gemcitabine for the Treatment of Pancreatic Cancer. U.S. National Institutes of Health.

REF 12

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800013965)

REF 13

REF 14

An epidemiologic study of abuse of analgesic drugs. Effects of phenacetin and salicylate on mortality and cardiovascular morbidity (1968 to 1987)Dubach UC1, Rosner B, St rmer T.Author information1Department of Internal Medicine, Kantonsspital, Basel, Switzerland.AbstractBACKGROUND: Phenacetin abuse is known to produce kidney disease; salicylate use is supposed to prevent cardiovascular disease. We conducted a prospective, longitudinal epidemiologic study to examine the effects of these drugs on cause-specific mortality and on cardiovascular morbidity.METHODS: In 1968 we evaluated a study group of 623 healthy women 30 to 49 years old who had evidence of a regular intake of phenacetin, as measured by urinary excretion of its metabolites, and a matched control group of 621 women. Salicylate excretion was also measured. All subjects were examined over a period of 20 years.RESULTS: Life-table analyses of mortality during the 20 years, with adjustment for the year of birth, cigarette smoking, and length of follow-up, revealed significant differences between the groups in overall mortality (study group vs. control group, 74 vs. 27 deaths; relative risk, 2.2; 95 percent confidence interval, 1.5 to 3.3), deaths due to urologic or renal disease (relative risk, 16.1; 95 percent confidence interval, 3.9 to 66.1), deaths due to cancer (relative risk, 1.9; 95 percent confidence interval, 1.1 to 3.3), and deaths due to cardiovascular disease (relative risk, 2.9; 95 percent confidence interval, 1.5 to 5.5). The relative risk of cardiovascular disease (fatal or nonfatal myocardial infarction, heart failure, or stroke) was 1.8, and the 95 percent confidence interval 1.3 to 2.6. The odds ratio for the incidence of hypertension was 1.6, and the 95 percent confidence interval 1.2 to 2.1. The effects of phenacetin on morbidity and mortality, with adjustment for base-line salicylate excretion, were similar. In contrast, salicylate use had no effect on either mortality or morbidity.CONCLUSIONS: Regular use of analgesic drugs containing phenacetin is associated with an increased risk of hypertension and mortality and morbidity due to cardiovascular disease, as well as an increased riskof mortality due to cancer and urologic or renal disease. The use of salicylates carries no such risk.Comment inThe risks of phenacetin use. [N Engl J Med. 1991]PMID: 1984193 [PubMed - indexed for MEDLINE] Free full textSharePublication Types, MeSH Terms, SubstancesPublication TypesResearch Support, Non-U.S. Gov'tMeSH TermsAdultAgedAspirin/adverse effects*Cardiovascular Diseases/epidemiology*Cardiovascular Diseases/mortalityDose-Response Relationship, DrugFemaleHumansHypertension/epidemiologyKidney Diseases/mortalityLongitudinal StudiesMiddle AgedMortality*Neoplasms/mortalityPhenacetin/adverse effects*Prospective StudiesRiskSubstance-Related Disorders*Urologic Diseases/mortalitySubstancesPhenacetinAspirinLinkOut - more resourcesFull Text SourcesAtypon - PDFAtyponOvid Technologies, Inc.MedicalDrug Abuse - MedlinePlus Health InformationMiscellaneousACETYLSALICYLIC ACID - Hazardous Substances Data BankPHENACETIN - Hazardous Substances Data BankPubMed Commons home N Engl J Med. 1991 Jan 17;324(3):155-60.

REF 15

VX-497: a novel, selective IMPDH inhibitor and immunosuppressive agent. J Pharm Sci. 2001 May;90(5):625-37.

REF 16

Inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitors: a patent and scientific literature review (2002-2016).Expert Opin Ther Pat. 2017 Jun;27(6):677-690.

REF 17

Cofactor 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 18

Treating HCV with ribavirin analogues and ribavirin-like molecules. J Antimicrob Chemother. 2006 Jan;57(1):8-13.

REF 19

A 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 20

In vitro and in vivo antiproliferative activity of IPCAR, a new pyrazole nucleoside analog. Anticancer Res. 1998 Jul-Aug;18(4A):2623-30.

REF 21

Sequential impact of tiazofurin and ribavirin on the enzymic program of the bone marrow. Cancer Res. 1993 Dec 15;53(24):5982-6.

REF 22

Relationships between the cytotoxicity of tiazofurin and its metabolism by cultured human lung cancer cells. J Clin Invest. 1985 Jan;75(1):175-82.

REF 23

Antiviral agents active against influenza A viruses. Nat Rev Drug Discov. 2006 Dec;5(12):1015-25.

REF 24

Characterization 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.

REF 25

A potent "fat base" nucleotide inhibitor of IMP dehydrogenase. Biochemistry. 1998 Aug 25;37(34):11949-52.

REF 26

Identification of the IMP binding site in the IMP dehydrogenase from Tritrichomonas foetus. Biochemistry. 1995 Oct 24;34(42):13889-94.

REF 27

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 28

Crystal 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.

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