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autotaxin

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2901

Nomenclature: autotaxin

Family: LPA synthesis

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 863 8q24.12 ENPP2 ectonucleotide pyrophosphatase/phosphodiesterase 2
Mouse - 862 15 D1 Enpp2 ectonucleotide pyrophosphatase/phosphodiesterase 2
Rat - 887 7q32 Enpp2 ectonucleotide pyrophosphatase/phosphodiesterase 2
Gene and Protein Information Comments
The table provides information for human variant 1, which is the longest transcript and encodes the longest isoform (1, also known as alpha). Similarly for the mouse gene, which has 4 reported transcript variants, we provide information for the longest protein isoform.
In humans and mice variant 2, which is translated to isoform β, is the major isoform found in tissue expression studies [7].
Previous and Unofficial Names Click here for help
ATX | PDNP2 | PD-IALPHA | lysoPLD
Database Links Click here for help
Alphafold Q13822 (Hs), Q9R1E6 (Mm), Q64610 (Rn)
BRENDA 3.1.4.39
CATH/Gene3D 3.40.720.10
ChEMBL Target CHEMBL3691 (Hs), CHEMBL3826871 (Mm), CHEMBL3826870 (Rn)
Ensembl Gene ENSG00000136960 (Hs), ENSMUSG00000022425 (Mm), ENSRNOG00000004089 (Rn)
Entrez Gene 5168 (Hs), 18606 (Mm), 84050 (Rn)
Human Protein Atlas ENSG00000136960 (Hs)
KEGG Enzyme 3.1.4.39
KEGG Gene hsa:5168 (Hs), mmu:18606 (Mm), rno:84050 (Rn)
OMIM 601060 (Hs)
Pharos Q13822 (Hs)
RefSeq Nucleotide NM_006209 (Hs), NM_001040092 (Hs), NM_001130863 (Hs), NM_001285994 (Mm), NM_001285995 (Mm), NM_015744 (Mm), NM_001136077 (Mm), NM_057104 (Rn)
RefSeq Protein NP_001124335 (Hs), NP_001035181 (Hs), NP_006200 (Hs), NP_001272923 (Mm), NP_056559 (Mm), NP_001129549 (Mm), NP_001272924 (Mm), NP_476445 (Rn)
UniProtKB Q13822 (Hs), Q9R1E6 (Mm), Q64610 (Rn)
Wikipedia ENPP2 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  A new Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis: A Clinical Candidate Discovered Using DNA-Encoded Chemistry
PDB Id:  6W35
Ligand:  X-165
Resolution:  1.98Å
Species:  Human
References:  4
Enzyme Reaction Click here for help
EC Number: 3.1.4.39
Description Reaction Reference
Hydrolysis of lysophosphatidylcholine to form lysophosphatidic acid 1-alkyl-sn-glycero-3-phosphoethanolamine + H2O <=> 1-alkyl-sn-glycerol 3-phosphate + ethanolamine

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
ziritaxestat Small molecule or natural product Primary target of this compound Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.8 pKi 5
⤷ pKi 7.8 (Ki 1.5x10-8 M) [5]
Description: Inhibition of substrate (LPC) conversion to LPA.
example 1.11 [WO2014139978] Small molecule or natural product Primary target of this compound Hs Inhibition 9.0 pIC50 9
⤷ pIC50 9.0 (IC50 1x10-9 M) [9]
PF-8380 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 8.6 – 8.8 pIC50 6,13
⤷ pIC50 8.6 – 8.8 (IC50 2.8x10-9 – 1.7x10-9 M) [6,13]
BI-2545 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.7 pIC50 10
⤷ pIC50 8.7 (IC50 2.2x10-9 M) [10]
example 2 [WO2013054185] Small molecule or natural product Primary target of this compound Hs Inhibition 8.6 pIC50 11
⤷ pIC50 8.6 (IC50 2.59x10-9 M) [11]
BI-2545 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Immunopharmacology Ligand Rn Inhibition 8.5 pIC50 10
⤷ pIC50 8.5 (IC50 3.4x10-9 M) [10]
example 31 (24) [WO2012005227] Small molecule or natural product Primary target of this compound Rn Inhibition 7.6 – 8.0 pIC50 1
⤷ pIC50 8.0 (IC50 1x10-8 M) [1]
Description: Evaluated in a rat whole blood assay.
pIC50 7.6 (IC50 2.7x10-8 M) [1]
Description: Evaluated in an in vitro biochemical ATX assay.
X-165 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 7.3 pIC50 4
⤷ pIC50 7.3 (IC50 5.5x10-8 M) [4]
Description: Determined by measuring inhibition of choline release from LPC 16:0 by recombinant human autotaxin.
inhibitor 32 [PMID: 29620892] Small molecule or natural product Immunopharmacology Ligand Mm Inhibition 7.2 pIC50 12
⤷ pIC50 7.2 (IC50 6x10-8 M) [12]
Description: Inhibition of purified mouse ATX-mediated production of choline from the cleavage of LPC to LPA.
BIO-32546 Small molecule or natural product Hs Inhibition >6.3 pIC50 8
⤷ pIC50 >6.3 (IC50 <5x10-7 M) [8]
Description: Determined in a biochemical FRET (fluorescence resonance energy transfer) enzyme activity assay
View species-specific inhibitor tables
Inhibitor Comments
ATX inhibitors are being investigated for potential anti-fibrotic activity. ATX inhibitor development and exemplar compounds are discussed in [2]. Ziritaxestat (GLPG1690) has completed a first-in-human Phase 1 clinical trial (NCT02179502). Phase 2 trial NCT02738801 is evaluating the safety, tolerability, PK and PD of GLPG1690 in patients with idiopathic pulmonary fibrosis (IPF). However, example 31 (24) (a.k.a. Ex_31) failed to show any anti-fibrotic effects in two models of advanced liver fibrosis in rats [1].
Immunopharmacology Comments
Autotaxin is up-regulated in many inflammatory conditions, including cancer, arthritis, fibrotic diseases and multiple sclerosis. The product of autotaxin activity, LPA, has proliferative, chemotactic and angiogenic actions. Inhibitors of the ATX-LPA axis are being investigated as novel pharmaceuticals [2].
Immuno Process Associations
Immuno Process:  Antigen presentation
Tissue Distribution Click here for help
Brain and peripheral tissues (human and mouse):
predominately ATXβ isoform. ATXα found at low levels in central and peripheral nervous systems, and ATXγ also at low levels in the CNS.
Species:  Human
Technique:  RT-PCR
References:  7
Physiological Functions Click here for help
Converts sphingosylphosphorylcholine (SPC) to sphingosine 1-phosphate (S1P)
Species:  Human
Tissue:  In vitro cell culture
References:  3
Hydrolyzes lysophosphatidylcholine to form the bioactive lipid lysophosphatidic acid (LPA).
Species:  Human
Tissue: 
References:  7

References

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1. Baader M, Bretschneider T, Broermann A, Rippmann JF, Stierstorfer B, Kuttruff CA, Mark M. (2018) Characterization of the properties of a selective, orally bioavailable autotaxin inhibitor in preclinical models of advanced stages of liver fibrosis. Br J Pharmacol, 175 (4): 693-707. [PMID:29197066]

2. Castagna D, Budd DC, Macdonald SJ, Jamieson C, Watson AJ. (2016) Development of Autotaxin Inhibitors: An Overview of the Patent and Primary Literature. J Med Chem, 59 (12): 5604-21. [PMID:26745766]

3. Clair T, Aoki J, Koh E, Bandle RW, Nam SW, Ptaszynska MM, Mills GB, Schiffmann E, Liotta LA, Stracke ML. (2003) Autotaxin hydrolyzes sphingosylphosphorylcholine to produce the regulator of migration, sphingosine-1-phosphate. Cancer Res, 63 (17): 5446-53. [PMID:14500380]

4. Cuozzo JW, Clark MA, Keefe AD, Kohlmann A, Mulvihill M, Ni H, Renzetti LM, Resnicow DI, Ruebsam F, Sigel EA et al.. (2020) Novel Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis: A Clinical Candidate Discovered Using DNA-Encoded Chemistry. J Med Chem, 63 (14): 7840-7856. [PMID:32584034]

5. Desroy N, Housseman C, Bock X, Joncour A, Bienvenu N, Cherel L, Labeguere V, Rondet E, Peixoto C, Grassot JM et al.. (2017) Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis. J Med Chem, 60 (9): 3580-3590. [PMID:28414242]

6. Gierse J, Thorarensen A, Beltey K, Bradshaw-Pierce E, Cortes-Burgos L, Hall T, Johnston A, Murphy M, Nemirovskiy O, Ogawa S et al.. (2010) A novel autotaxin inhibitor reduces lysophosphatidic acid levels in plasma and the site of inflammation. J Pharmacol Exp Ther, 334 (1): 310-7. [PMID:20392816]

7. Giganti A, Rodriguez M, Fould B, Moulharat N, Cogé F, Chomarat P, Galizzi JP, Valet P, Saulnier-Blache JS, Boutin JA et al.. (2008) Murine and human autotaxin alpha, beta, and gamma isoforms: gene organization, tissue distribution, and biochemical characterization. J Biol Chem, 283 (12): 7776-89. [PMID:18175805]

8. Guckian K, Kumaravel G, Ma B, Mi S, Peng H, Shao Z, Sun L, Taveras A, Wang D, Xin Z, Zhang L. (2014) Atx modulating agents. Patent number: WO2014018881A1. Assignee: Biogen Idec Ma Inc.. Priority date: 27/07/2012. Publication date: 30/01/2014.

9. Hert J, Hunziker D, Mattei P, Mauser H, Tang G, Wang L. (2014) New octahydro-pyrrolo[3,4-c]-pyrrole derivatives and analogs thereof as autotaxin inhibitors. Patent number: WO2014139978 A1. Assignee: Hoffmann-La Roche Inc.. Priority date: 12/03/2013. Publication date: 18/09/2014.

10. Kuttruff CA, Ferrara M, Bretschneider T, Hoerer S, Handschuh S, Nosse B, Romig H, Nicklin P, Roth GJ. (2017) Discovery of BI-2545: A Novel Autotaxin Inhibitor That Significantly Reduces LPA Levels in Vivo. ACS Med Chem Lett, 8 (12): 1252-1257. [PMID:29259743]

11. Long S, Thorarensen A, Schnute ME. (2013) Pyrimidine and pyridine derivatives useful in therapy. Patent number: WO2013054185 A1. Assignee: Pfizer, Inc.. Priority date: 13/10/2011. Publication date: 18/04/2013.

12. Nikolaou A, Ninou I, Kokotou MG, Kaffe E, Afantitis A, Aidinis V, Kokotos G. (2018) Hydroxamic Acids Constitute a Novel Class of Autotaxin Inhibitors that Exhibit in Vivo Efficacy in a Pulmonary Fibrosis Model. J Med Chem, 61 (8): 3697-3711. [PMID:29620892]

13. St-Cœur PD, Ferguson D, Morin Jr P, Touaibia M. (2013) PF-8380 and closely related analogs: synthesis and structure-activity relationship towards autotaxin inhibition and glioma cell viability. Arch Pharm (Weinheim), 346 (2): 91-7. [PMID:23300119]

How to cite this page

LPA synthesis: autotaxin. Last modified on 01/07/2021. Accessed on 16/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2901.