Target Information
| Target General Information | Top | |||||
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| Target ID |
T63512
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| Target Name |
Extracellular lysophospholipase D (E-NPP2)
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| Synonyms |
LysoPLD; Ectonucleotide pyrophosphatase/phosphodiesterase family member 2; E-NPP 2; Autotaxin; ATX
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| Gene Name |
ENPP2
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Idiopathic interstitial pneumonitis [ICD-11: CB03] | |||||
| Function |
Hydrolyzes lysophospholipids to produce the signaling molecule lysophosphatidic acid (LPA) in extracellular fluids. Major substrate is lysophosphatidylcholine. Also can act on sphingosylphosphorylcholine producing sphingosine-1-phosphate, a modulator of cell motility. Can hydrolyze, in vitro, bis-pNPP, to some extent pNP-TMP, and barely ATP. Involved in several motility-related processes such as angiogenesis and neurite outgrowth. Acts as an angiogenic factor by stimulating migration of smooth muscle cells and microtubule formation. Stimulates migration of melanoma cells, probably via a pertussis toxin-sensitive G protein. May have a role in induction of parturition. Possible involvement in cell proliferation and adipose tissue development (Probable). Tumor cell motility-stimulating factor.
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| BioChemical Class |
Phosphoric diester hydrolase
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| UniProt ID | ||||||
| EC Number |
EC 3.1.4.39
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| Sequence |
MARRSSFQSCQIISLFTFAVGVNICLGFTAHRIKRAEGWEEGPPTVLSDSPWTNISGSCK
GRCFELQEAGPPDCRCDNLCKSYTSCCHDFDELCLKTARGWECTKDRCGEVRNEENACHC SEDCLARGDCCTNYQVVCKGESHWVDDDCEEIKAAECPAGFVRPPLIIFSVDGFRASYMK KGSKVMPNIEKLRSCGTHSPYMRPVYPTKTFPNLYTLATGLYPESHGIVGNSMYDPVFDA TFHLRGREKFNHRWWGGQPLWITATKQGVKAGTFFWSVVIPHERRILTILQWLTLPDHER PSVYAFYSEQPDFSGHKYGPFGPEMTNPLREIDKIVGQLMDGLKQLKLHRCVNVIFVGDH GMEDVTCDRTEFLSNYLTNVDDITLVPGTLGRIRSKFSNNAKYDPKAIIANLTCKKPDQH FKPYLKQHLPKRLHYANNRRIEDIHLLVERRWHVARKPLDVYKKPSGKCFFQGDHGFDNK VNSMQTVFVGYGSTFKYKTKVPPFENIELYNVMCDLLGLKPAPNNGTHGSLNHLLRTNTF RPTMPEEVTRPNYPGIMYLQSDFDLGCTCDDKVEPKNKLDELNKRLHTKGSTEERHLLYG RPAVLYRTRYDILYHTDFESGYSEIFLMPLWTSYTVSKQAEVSSVPDHLTSCVRPDVRVS PSFSQNCLAYKNDKQMSYGFLFPPYLSSSPEAKYDAFLVTNMVPMYPAFKRVWNYFQRVL VKKYASERNGVNVISGPIFDYDYDGLHDTEDKIKQYVEGSSIPVPTHYYSIITSCLDFTQ PADKCDGPLSVSSFILPHRPDNEESCNSSEDESKWVEELMKMHTARVRDIEHLTSLDFFR KTSRSYPEILTLKTYLHTYESEI Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | Cudetaxestat | Drug Info | Phase 2 | Idiopathic pulmonary fibrosis | [2] | |
| Patented Agent(s) | [+] 3 Patented Agents | + | ||||
| 1 | Complex heterocyclic compound 1 | Drug Info | Patented | Inflammation | [1] | |
| 2 | Pyridine and pyrimidine derivative 1 | Drug Info | Patented | Fibrosis | [1] | |
| 3 | Pyrido/pyrrolo-fused pyrimidine derivative 1 | Drug Info | Patented | Pain | [1] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 22 Inhibitor drugs | + | ||||
| 1 | Cudetaxestat | Drug Info | [3] | |||
| 2 | Complex heterocyclic compound 1 | Drug Info | [1] | |||
| 3 | Dihydropyrido pyrimidine derivative 1 | Drug Info | [1] | |||
| 4 | Heteroaromatic ring derivative 1 | Drug Info | [1] | |||
| 5 | Heteroaromatic ring derivative 2 | Drug Info | [1] | |||
| 6 | Heteroaromatic ring derivative 3 | Drug Info | [1] | |||
| 7 | Heteroaromatic ring derivative 4 | Drug Info | [1] | |||
| 8 | Imidazopyrimidinone derivative 1 | Drug Info | [1] | |||
| 9 | Octahydro-pyrrolo[3,4-c]-pyrrole derivative 1 | Drug Info | [1] | |||
| 10 | PMID28447479-Compound-10 | Drug Info | [1] | |||
| 11 | PMID28447479-Compound-11 | Drug Info | [1] | |||
| 12 | PMID28447479-Compound-14 | Drug Info | [1] | |||
| 13 | PMID28447479-Compound-20 | Drug Info | [1] | |||
| 14 | PMID28447479-Compound-21 | Drug Info | [1] | |||
| 15 | PMID28447479-Compound-4 | Drug Info | [1] | |||
| 16 | Pyrazole derivative 87 | Drug Info | [1] | |||
| 17 | Pyrazolo[3,4-c]pyridine derivative 1 | Drug Info | [1] | |||
| 18 | Pyridine and pyrimidine derivative 1 | Drug Info | [1] | |||
| 19 | Pyrido/pyrrolo-fused pyrimidine derivative 1 | Drug Info | [1] | |||
| 20 | Pyrimidinone derivative 5 | Drug Info | [1] | |||
| 21 | Tetra-hydro-carboline derivative 1 | Drug Info | [1] | |||
| 22 | Tetra-hydro-carboline derivative 2 | Drug Info | [1] | |||
| Agonist | [+] 2 Agonist drugs | + | ||||
| 1 | PMID28447479-Compound-26 | Drug Info | [1] | |||
| 2 | PMID28447479-Compound-27 | Drug Info | [1] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Arachidonic acid | Ligand Info | |||||
| Structure Description | Structural basis for inhibition of human autotaxin by four novel compounds | PDB:4ZGA | ||||
| Method | X-ray diffraction | Resolution | 2.60 Å | Mutation | No | [4] |
| PDB Sequence |
GSCKGRCFEL
66 CRCDNLCKSY83 TSCCHDFDEL93 CLKTARGWEC103 TKDRCGNEEN116 ACHCEDCLAR 127 GDCCTNYQVV137 CKGESHWVDD147 DCEEIKAAEC157 PAGFVRPPLI167 IFSVDGFRAS 177 YMKKGSKVMP187 NIEKLRSCGT197 HSPYMRPVYP207 TKTFPNLYTL217 ATGLYPESHG 227 IVGNSMYDPV237 FDATFHLRGR247 EKFNHRWWGG257 QPLWITATKQ267 GVKAGTFFWS 277 VVIPHERRIL287 TILQWLTLPD297 HERPSVYAFY307 SEQPDFSGHK317 YGPFGPEMTN 327 PLREIDKIVG337 QLMDGLKQLK347 LHRCVNVIFV357 GDHGMEDVTC367 DRTEFLSNYL 377 TNVDDITLVP387 GTLGRIRSKF397 DPKAIIANLT413 CKKPDQHFKP423 YLKQHLPKRL 433 HYANNRRIED443 IHLLVERRWH453 VARKPFFQGD474 HGFDNKVNSM484 QTVFVGYGST 494 FKYKTKVPPF504 ENIELYNVMC514 DLLGLKPAPN524 NGTHGSLNHL534 LRTNTFRPTM 544 PEEVTRPNYP554 GIMYLQSDFD564 LGTEERHLLY599 GRPAVLYRTR609 YDILYHTDFE 619 SGYSEIFLMP629 LWTSYTVSKQ639 ACVRPDVRVS660 PSFSQNCLAY670 KNDKQMSYGF 680 LFPPYLSSSP690 EAKYDAFLVT700 NMVPMYPAFK710 RVWNYFQRVL720 VKKYASERNG 730 VNVISGPIFD740 YDYDGLHDTE750 DKIKQYVEGS760 SIPVPTHYYS770 IITSCLDFTQ 780 PADKCDGPLS790 VSSFILPHRP800 DNEESCNSSE810 DESKWVEELM820 KMHTARVRDI 830 EHLTSLDFFR840 KTSRSYPEIL850 TLKTYLHTYE860
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| Ligand Name: 3-[6-Chloranyl-2-Cyclopropyl-1-(1-Ethylpyrazol-4-Yl)-7-Fluoranyl-Indol-3-Yl]sulfanyl-2-Fluoranyl-Benzoic Acid | Ligand Info | |||||
| Structure Description | Selective Inhibition of Autotaxin is Effective in Mouse Models of Liver Fibrosis | PDB:5KXA | ||||
| Method | X-ray diffraction | Resolution | 2.59 Å | Mutation | Yes | [5] |
| PDB Sequence |
GSCKGRCFEL
66 QCRCDNLCKS82 YTSCCHDFDE92 LCLKTARGWE102 CTKDRCGEVR112 NEENACHCSE 122 DCLARGDCCT132 NYQVVCKGES142 HWVDDDCEEI152 KAAECPAGFV162 RPPLIIFSVD 172 GFRASYMKKG182 SKVMPNIEKL192 RSCGTHSPYM202 RPVYPTKTFP212 NLYTLATGLY 222 PESHGIVGNS232 MYDPVFDATF242 HLRGREKFNH252 RWWGGQPLWI262 TATKQGVKAG 272 TFFWSVVIPH282 ERRILTILQW292 LTLPDHERPS302 VYAFYSEQPD312 FSGHKYGPFG 322 PEMTNPLREI332 DKIVGQLMDG342 LKQLKLHRCV352 NVIFVGDHGM362 EDVTCDRTEF 372 LSNYLTNVDD382 ITLVPGTLGR392 IRSKFSNNAK402 YDPKAIIAAL412 TCKKPDQHFK 422 PYLKQHLPKR432 LHYANNRRIE442 DIHLLVERRW452 HVARKPFFQG473 DHGFDNKVNS 483 MQTVFVGYGS493 TFKYKTKVPP503 FENIELYNVM513 CDLLGLKPAP523 NNGTHGSLNH 533 LLRTNTFRPT543 MPEEVTRPNY553 PGIMYLQSDF563 DLGTEERHLL598 YGRPAVLYRT 608 RYDILYHTDF618 ESGYSEIFLM628 PLWTSYTVSK638 QACVRPDVRV659 SPSFSQNCLA 669 YKNDKQMSYG679 FLFPPYLSSS689 PEAKYDAFLV699 TNMVPMYPAF709 KRVWNYFQRV 719 LVKKYASERN729 GVNVISGPIF739 DYDYDGLHDT749 EDKIKQYVEG759 SSIPVPTHYY 769 SIITSCLDFT779 QPADKCDGPL789 SVSSFILPHR799 PDNEESCNSS809 EDESKWVEEL 819 MKMHTARVRD829 IEHLTSLDFF839 RKTSRSYPEI849 LTLKTYLHTY859 E |
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Ether lipid metabolism | hsa00565 | Affiliated Target |
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| Class: Metabolism => Lipid metabolism | Pathway Hierarchy | ||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "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 | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Ether lipid metabolism | |||||
| References | Top | |||||
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| REF 1 | Autotaxin inhibitors: a patent review (2012-2016).Expert Opin Ther Pat. 2017 Jul;27(7):815-829. | |||||
| REF 2 | ClinicalTrials.gov (NCT05373914) RESPIRARE - A Phase 2, Randomized, Double-blinded, Placebo-controlled, Efficacy and Safety Study of Cudetaxestat (BLD-0409) Assessed Across Three Dose Ranges With or Without Standard of Care (Nintedanib or Pirfenidone) in Patients With Idiopathic Pulmonary Fibrosis (IPF). U.S.National Institutes of Health. | |||||
| REF 3 | An updated patent review of autotaxin inhibitors (2017-present). Expert Opin Ther Pat. 2021 May;31(5):421-434. | |||||
| REF 4 | Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding. Mol Pharmacol. 2015 Dec;88(6):982-92. | |||||
| REF 5 | Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis. J Pharmacol Exp Ther. 2017 Jan;360(1):1-13. | |||||
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