Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT9SL3Q)

• DTT Name: Polypeptide deformylase (PDF)
• Synonyms: PDF
• Gene Name: PDF
• DTT Type: Successful target; [1]
• Related Disease:
  Anxiety disorder [ICD-11: 6B00-6B0Z]
  Breast cancer [ICD-11: 2C60-2C6Y]
  Malaria [ICD-11: 1F40-1F45]
  Mature T-cell lymphoma [ICD-11: 2A90]
  Psoriasis [ICD-11: EA90]
  Toxoplasmosis [ICD-11: 1F57]
• BioChemical Class: CH-NH donor oxidoreductase
• UniProt ID: DEFM_HUMAN
• TTD ID: T89515
• EC Number: EC 3.5.1.88
• Sequence:
  MARLWGALSLWPLWAAVPWGGAAAVGVRACSSTAAPDGVEGPALRRSYWRHLRRLVLGPP
  EPPFSHVCQVGDPVLRGVAAPVERAQLGGPELQRLTQRLVQVMRRRRCVGLSAPQLGVPR
  QVLALELPEALCRECPPRQRALRQMEPFPLRVFVNPSLRVLDSRLVTFPEGCESVAGFLA
  CVPRFQAVQISGLDPNGEQVVWQASGWAARIIQHEMDHLQGCLFIDKMDSRTFTNVYWMK
  VND
• Function: Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, DNA precursor synthesis, and for the conversion of dUMP to dTMP.
• Reactome Pathway:
  Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation (R-HSA-1474151)
  Metabolism of folate and pterines (R-HSA-196757)
  G1/S-Specific Transcription (R-HSA-69205)
  E2F mediated regulation of DNA replication (R-HSA-113510)

Molecular Interaction Atlas (MIA) of This DTT

7 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Chlorproguanil	DM1IFGT	Malaria	1F40-1F45	Approved	[1]
MCB-3837	DM0R4Z5	Malaria	1F40-1F45	Approved	[1], [2]
Meprobamate	DMHM93Y	Anxiety disorder	6B00-6B0Z	Approved	[1]
Pralatrexate	DMAO80I	Breast cancer	2C60-2C65	Approved	[3]
Proguanil	DMBL79I	Malaria	1F40-1F45	Approved	[4]
Trimetrexate	DMDEA85	Toxoplasmosis	1F57	Approved	[5], [6]
Ustekinumab	DMHTYK3	Plaque psoriasis	EA90.0	Approved	[7], [4]

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
LY333531	DMGMC8H	Solid tumour/cancer	2A00-2F9Z	Phase 2	[8]
Metoprine	DM5GQD7	Advanced cancer	2A00-2F9Z	Phase 2	[9]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Aminopterin	DMQ9RBV	leukaemia	2A60-2B33	Withdrawn from market	[10], [11]

56 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2'-Monophosphoadenosine 5'-Diphosphoribose	DME9S8M	Discovery agent	N.A.	Investigative	[12]
2'-Monophosphoadenosine-5'-Diphosphate	DMDYRNF	Discovery agent	N.A.	Investigative	[12]
2-(N-Morpholino)-Ethanesulfonic Acid	DMZVHSB	Discovery agent	N.A.	Investigative	[12]
2-Allylthio-3-benzyl-6-nitro-quinazolin-4(3H)-one	DMTO1EJ	Discovery agent	N.A.	Investigative	[13]
2-Allylthio-6-amino-3-benzyl-quinazolin-4(3H)-one	DMBWGCX	Discovery agent	N.A.	Investigative	[13]
2-Sulfhydryl-Ethanol	DMJBO3D	Discovery agent	N.A.	Investigative	[12]
3-Benzyl-2-ethylthio-6-nitro-quinazolin-4(3H)-one	DMQ13Z8	Discovery agent	N.A.	Investigative	[13]
3-benzyl-2-mercapto-6-nitroquinazolin-4(3H)-one	DM4GWAH	Discovery agent	N.A.	Investigative	[13]
3-Phenylsulfanylmethyl-quinoxaline-5,7-diamine	DMRNHXE	Discovery agent	N.A.	Investigative	[14]
4-(2,6-diamino-9H-purin-8-yl)-2,6-dimethoxyphenol	DMH3TBQ	Discovery agent	N.A.	Investigative	[15]
5-((E)-Styryl)-quinazoline-2,4-diamine	DMH0QA7	Discovery agent	N.A.	Investigative	[16]
5-(2-fluorobenzyloxy)quinazoline-2,4-diamine	DMQCYEK	Discovery agent	N.A.	Investigative	[17]
5-(4-Methoxyphenoxy)-2,4-Quinazolinediamine	DM3SQEY	Discovery agent	N.A.	Investigative	[12]
5-Chloryl-2,4,6-Quinazolinetriamine	DMWS3D6	Discovery agent	N.A.	Investigative	[12]
5-Formyl-6-Hydrofolic Acid	DM371WE	Discovery agent	N.A.	Investigative	[12]
5-p-Tolylsulfanyl-quinazoline-2,4-diamine	DMV4ICS	Discovery agent	N.A.	Investigative	[18]
5-Phenethyl-quinazoline-2,4-diamine	DMWI7XJ	Discovery agent	N.A.	Investigative	[16]
5-Phenylsulfanyl-2,4-Quinazolinediamine	DMMWYFR	Discovery agent	N.A.	Investigative	[12], [18]
6,7-Diphenyl-pteridine-2,4-diamine	DM7U8ID	Discovery agent	N.A.	Investigative	[19]
6-(2-Phenylsulfanyl-ethyl)-pteridine-2,4-diamine	DMKXNP0	Discovery agent	N.A.	Investigative	[19]
6-m-Tolyl-pteridine-2,4,7-triamine	DMHU78R	Discovery agent	N.A.	Investigative	[19]
6-Phenylaminomethyl-quinazoline-2,4-diamine	DMG6PZT	Discovery agent	N.A.	Investigative	[20]
6-Phenylsulfanylmethyl-pteridine-2,4-diamine	DM6GWRB	Discovery agent	N.A.	Investigative	[21]
7-Methyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine	DMZKO14	Discovery agent	N.A.	Investigative	[22]
7H-Pyrrolo[3,2-f]quinazoline-1,3-diamine	DMEGSZD	Discovery agent	N.A.	Investigative	[22]
8-(2,3,4-trimethoxyphenyl)-9H-purine-2,6-diamine	DM3QV95	Discovery agent	N.A.	Investigative	[15]
8-(2,4,5-trimethoxyphenyl)-9H-purine-2,6-diamine	DM4KP5M	Discovery agent	N.A.	Investigative	[15]
8-(2,4,6-trimethoxyphenyl)-9H-purine-2,6-diamine	DM5TSJF	Discovery agent	N.A.	Investigative	[15]
8-(2,4-dimethoxyphenyl)-9H-purine-2,6-diamine	DMJPYIZ	Discovery agent	N.A.	Investigative	[15]
8-(2,5-dimethoxyphenyl)-9H-purine-2,6-diamine	DM0MIGU	Discovery agent	N.A.	Investigative	[15]
8-(2,6-Dichloro-phenyl)-9H-purine-2,6-diamine	DMECWL1	Discovery agent	N.A.	Investigative	[23]
8-(3,4,5-trimethoxyphenyl)-9H-purine-2,6-diamine	DMV63G1	Discovery agent	N.A.	Investigative	[15]
8-(3,4-dichlorophenyl)-9H-purine-2,6-diamine	DMZU0YF	Discovery agent	N.A.	Investigative	[15]
8-(3,4-dimethoxyphenyl)-9H-purine-2,6-diamine	DMYZC3I	Discovery agent	N.A.	Investigative	[15]
8-(3,5-dimethoxyphenyl)-9H-purine-2,6-diamine	DM920XR	Discovery agent	N.A.	Investigative	[15]
8-benzyl-9H-purine-2,6-diamine	DM32OQB	Discovery agent	N.A.	Investigative	[15]
8-Pyridin-4-yl-9H-purine-2,6-diamine	DM1I25F	Discovery agent	N.A.	Investigative	[23]
Biopterin	DMLNQ2F	Discovery agent	N.A.	Investigative	[12]
Brodimoprim-4,6-Dicarboxylate	DM7OF6N	Discovery agent	N.A.	Investigative	[12]
Bromo-WR99210	DMKFTW8	Discovery agent	N.A.	Investigative	[12]
Cycloguanil	DMC520D	Malaria	1F40-1F45	Investigative	[24]
DDATHF	DM6GWAC	Discovery agent	N.A.	Investigative	[12]
Dihydrofolic Acid	DM1BDM8	Discovery agent	N.A.	Investigative	[12]
Edatrexate	DM32O0L	Discovery agent	N.A.	Investigative	[10]
Furo[2,3d]Pyrimidine Antifolate	DMVYEZ1	Discovery agent	N.A.	Investigative	[12]
GNF-PF-173	DMUSAYG	Discovery agent	N.A.	Investigative	[25]
GNF-PF-607	DMJXE6K	Discovery agent	N.A.	Investigative	[26]
N*6*-Benzyl-quinazoline-2,4,6-triamine	DMRNGV0	Discovery agent	N.A.	Investigative	[26]
NB3178	DMNM6GQ	Gram-positive bacterial infection	1B74-1G40	Investigative	[27]
NB3322	DMJHWGS	Gram-positive bacterial infection	1B74-1G40	Investigative	[27]
Pergularinine	DM8OC9F	Discovery agent	N.A.	Investigative	[28]
PREMETREXED	DMVOGT4	Discovery agent	N.A.	Investigative	[29]
Ro 5-4864	DMTQP0K	Gram-positive bacterial infection	1B74-1G40	Investigative	[27]
Sri-9439	DM5GILS	Discovery agent	N.A.	Investigative	[30]
Sri-9662	DMYO4A3	Discovery agent	N.A.	Investigative	[12]
Tylophorinidine	DMHFCZA	Discovery agent	N.A.	Investigative	[28]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Acute myelocytic leukaemia	2C82	Bone marrow	8.87E-16	-0.54	-0.86
Rheumatoid arthritis	FA20	Synovial tissue	1.08E-02	0.38	1.46
Bladder cancer	2C82	Bladder tissue	5.11E-06	0.97	3.88

References

• [1] The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr Med Chem. 2008;15(2):161-71.
• [2] How many modes of action should an antibiotic have Curr Opin Pharmacol. 2008 Oct;8(5):564-73.
• [3] Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92.
• [4] Transformation with human dihydrofolate reductase renders malaria parasites insensitive to WR99210 but does not affect the intrinsic activity of proguanil. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10931-6.
• [5] Expression and characterization of recombinant human-derived Pneumocystis carinii dihydrofolate reductase. Antimicrob Agents Chemother. 2000 Nov;44(11):3092-6.
• [6] Synthesis and biological activities of tricyclic conformationally restricted tetrahydropyrido annulated furo[2,3-d]pyrimidines as inhibitors of dihydrofolate reductases. J Med Chem. 1998 Apr 23;41(9):1409-16.
• [7] Novel Saccharomyces cerevisiae screen identifies WR99210 analogues that inhibit Mycobacterium tuberculosis dihydrofolate reductase. Antimicrob Agents Chemother. 2002 Nov;46(11):3362-9.
• [8] Three-dimensional structure of M. tuberculosis dihydrofolate reductase reveals opportunities for the design of novel tuberculosis drugs. J Mol Biol. 2000 Jan 14;295(2):307-23.
• [9] Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates. Cancer Chemother Pharmacol. 2006 Dec;58(6):826-34.
• [10] Loss of folylpoly-gamma-glutamate synthetase activity is a dominant mechanism of resistance to polyglutamylation-dependent novel antifolates in multiple human leukemia sublines. Int J Cancer. 2003 Feb 20;103(5):587-99.
• [11] vestigial suppressor genes and resistance to aminopterin in Drosophila melanogaster. Heredity. 1992 Nov;69 ( Pt 5):473-7.
• [12] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [13] Non-classical antifolates. Part 2: synthesis, biological evaluation, and molecular modeling study of some new 2,6-substituted-quinazolin-4-ones. Bioorg Med Chem. 2010 Apr 15;18(8):2849-63.
• [14] New drug developments for opportunistic infections in immunosuppressed patients: Pneumocystis carinii. J Med Chem. 1995 Nov 24;38(24):4739-59.
• [15] CoMFA analysis of tgDHFR and rlDHFR based on antifolates with 6-5 fused ring system using the all-orientation search (AOS) routine and a modified c... Bioorg Med Chem. 2010 Feb 15;18(4):1684-701.
• [16] 2,4-Diamino-5-substituted-quinazolines as inhibitors of a human dihydrofolate reductase with a site-directed mutation at position 22 and of the dih... J Med Chem. 1995 Mar 3;38(5):745-52.
• [17] Synthesis and biological evaluation of novel 2,4-diaminoquinazoline derivatives as SMN2 promoter activators for the potential treatment of spinal m... J Med Chem. 2008 Feb 14;51(3):449-69.
• [18] X-Ray crystal structures of Candida albicans dihydrofolate reductase: high resolution ternary complexes in which the dihydronicotinamide moiety of ... J Med Chem. 2001 Aug 30;44(18):2928-32.
• [19] Further studies on 2,4-diamino-5-(2',5'-disubstituted benzyl)pyrimidines as potent and selective inhibitors of dihydrofolate reductases from three ... J Med Chem. 2003 Apr 24;46(9):1726-36.
• [20] Design and synthesis of dihydrofolate reductase inhibitors encompassing a bridging ester group. Evaluation in a mouse colitis model. J Med Chem. 2003 Jul 31;46(16):3455-62.
• [21] Nonclassical 2,4-diamino-8-deazafolate analogues as inhibitors of dihydrofolate reductases from rat liver, Pneumocystis carinii, and Toxoplasma gon... J Med Chem. 1996 Apr 26;39(9):1836-45.
• [22] High-affinity inhibitors of dihydrofolate reductase: antimicrobial and anticancer activities of 7,8-dialkyl-1,3-diaminopyrrolo[3,2-f]quinazolines w... J Med Chem. 1996 Feb 16;39(4):892-903.
• [23] Conformationally restricted analogues of trimethoprim: 2,6-diamino-8-substituted purines as potential dihydrofolate reductase inhibitors from Pneum... J Med Chem. 1997 Sep 12;40(19):3032-9.
• [24] Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005 Sep;4(9):727-40.
• [25] Synthesis and biological evaluation of poly-gamma-glutamyl metabolites of 10-deazaaminopterin and 10-ethyl-10-deazaaminopterin. J Med Chem. 1988 Jan;31(1):181-5.
• [26] CoMFA and CoMSIA analyses of Pneumocystis carinii dihydrofolate reductase, Toxoplasma gondii dihydrofolate reductase, and rat liver dihydrofolate r... J Med Chem. 2005 Mar 10;48(5):1448-69.
• [27] Emerging drugs for bacterial urinary tract infections. Expert Opin Emerg Drugs. 2005 May;10(2):275-98.
• [28] Inhibition of dihydrofolate reductase and cell growth activity by the phenanthroindolizidine alkaloids pergularinine and tylophorinidine: the in vitro cytotoxicity of these plant alkaloids and their potential as antimicrobial and anticancer agents. Toxicol In Vitro. 2000 Feb;14(1):53-9.
• [29] Synthesis, antifolate, and antitumor activities of classical and nonclassical 2-amino-4-oxo-5-substituted-pyrrolo[2,3-d]pyrimidines. J Med Chem. 2001 Jun 7;44(12):1993-2003.
• [30] DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.