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5mhp

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Novel Imidazo[1,2-a]pyridine Derivatives with Potent Autotaxin/ENPP2 Inhibitor Activity

Structural highlights

5mhp is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.43Å
Ligands:	, , , , , , , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ENPP2_HUMAN Hydrolyzes lysophospholipids to produce lysophosphatidic acid (LPA) in extracellular fluids. Major substrate is lysophosphatidylcholine. Also can act on sphingosylphosphphorylcholine 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. Tumor cell motility-stimulating factor.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Autotaxin is a circulating enzyme with a major role in the production of lysophosphatic acid (LPA) species in blood. A role for the autotaxin/LPA axis has been suggested in many disease areas including pulmonary fibrosis. Structural modifications of the known autotaxin inhibitor lead compound 1, to attenuate hERG inhibition, remove CYP3A4 time-dependent inhibition, and improve pharmacokinetic properties, led to the identification of clinical candidate GLPG1690 (11). Compound 11 was able to cause a sustained reduction of LPA levels in plasma in vivo and was shown to be efficacious in a bleomycin-induced pulmonary fibrosis model in mice and in reducing extracellular matrix deposition in the lung while also reducing LPA 18:2 content in bronchoalveolar lavage fluid. Compound 11 is currently being evaluated in an exploratory phase 2a study in idiopathic pulmonary fibrosis patients.

Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methyli midazo[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.,Desroy N, Housseman C, Bock X, Joncour A, Bienvenu N, Cherel L, Labeguere V, Rondet E, Peixoto C, Grassot JM, Picolet O, Annoot D, Triballeau N, Monjardet A, Wakselman E, Roncoroni V, Le Tallec S, Blanque R, Cottereaux C, Vandervoort N, Christophe T, Mollat P, Lamers M, Auberval M, Hrvacic B, Ralic J, Oste L, van der Aar E, Brys R, Heckmann B J Med Chem. 2017 May 11;60(9):3580-3590. doi: 10.1021/acs.jmedchem.7b00032. Epub , 2017 May 1. PMID:28414242^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Nam SW, Clair T, Kim YS, McMarlin A, Schiffmann E, Liotta LA, Stracke ML. Autotaxin (NPP-2), a metastasis-enhancing motogen, is an angiogenic factor. Cancer Res. 2001 Sep 15;61(18):6938-44. PMID:11559573
↑ Stracke ML, Krutzsch HC, Unsworth EJ, Arestad A, Cioce V, Schiffmann E, Liotta LA. Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein. J Biol Chem. 1992 Feb 5;267(4):2524-9. PMID:1733949
↑ Hausmann J, Kamtekar S, Christodoulou E, Day JE, Wu T, Fulkerson Z, Albers HM, van Meeteren LA, Houben AJ, van Zeijl L, Jansen S, Andries M, Hall T, Pegg LE, Benson TE, Kasiem M, Harlos K, Kooi CW, Smyth SS, Ovaa H, Bollen M, Morris AJ, Moolenaar WH, Perrakis A. Structural basis of substrate discrimination and integrin binding by autotaxin. Nat Struct Mol Biol. 2011 Feb;18(2):198-204. Epub 2011 Jan 16. PMID:21240271 doi:10.1038/nsmb.1980
↑ Desroy N, Housseman C, Bock X, Joncour A, Bienvenu N, Cherel L, Labeguere V, Rondet E, Peixoto C, Grassot JM, Picolet O, Annoot D, Triballeau N, Monjardet A, Wakselman E, Roncoroni V, Le Tallec S, Blanque R, Cottereaux C, Vandervoort N, Christophe T, Mollat P, Lamers M, Auberval M, Hrvacic B, Ralic J, Oste L, van der Aar E, Brys R, Heckmann B. Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methyli midazo[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. 2017 May 11;60(9):3580-3590. doi: 10.1021/acs.jmedchem.7b00032. Epub , 2017 May 1. PMID:28414242 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b00032

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5mhp"

@@ Line 1: / Line 1: @@
 ==Novel Imidazo[1,2-a]pyridine Derivatives with Potent Autotaxin/ENPP2 Inhibitor Activity==
-<StructureSection load='5mhp' size='340' side='right' caption='[[5mhp]], [[Resolution|resolution]] 2.43&Aring;' scene=''>
+<StructureSection load='5mhp' size='340' side='right'caption='[[5mhp]], [[Resolution|resolution]] 2.43&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5mhp]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MHP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MHP FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5mhp]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MHP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MHP FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7NB:2-[[2-ethyl-8-methyl-6-[4-[2-(3-oxidanylazetidin-1-yl)-2-oxidanylidene-ethyl]piperazin-1-yl]imidazo[1,2-a]pyridin-3-yl]-methyl-amino]-4-(4-fluorophenyl)-1,3-thiazole-5-carbonitrile'>7NB</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.43&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Alkylglycerophosphoethanolamine_phosphodiesterase Alkylglycerophosphoethanolamine phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.39 3.1.4.39] </span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7NB:2-[[2-ethyl-8-methyl-6-[4-[2-(3-oxidanylazetidin-1-yl)-2-oxidanylidene-ethyl]piperazin-1-yl]imidazo[1,2-a]pyridin-3-yl]-methyl-amino]-4-(4-fluorophenyl)-1,3-thiazole-5-carbonitrile'>7NB</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5mhp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mhp OCA], [http://pdbe.org/5mhp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mhp RCSB], [http://www.ebi.ac.uk/pdbsum/5mhp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mhp ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5mhp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mhp OCA], [https://pdbe.org/5mhp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mhp RCSB], [https://www.ebi.ac.uk/pdbsum/5mhp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mhp ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/ENPP2_HUMAN ENPP2_HUMAN]] Hydrolyzes lysophospholipids to produce lysophosphatidic acid (LPA) in extracellular fluids. Major substrate is lysophosphatidylcholine. Also can act on sphingosylphosphphorylcholine 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. Tumor cell motility-stimulating factor.<ref>PMID:11559573</ref> <ref>PMID:1733949</ref> <ref>PMID:21240271</ref>
+[https://www.uniprot.org/uniprot/ENPP2_HUMAN ENPP2_HUMAN] Hydrolyzes lysophospholipids to produce lysophosphatidic acid (LPA) in extracellular fluids. Major substrate is lysophosphatidylcholine. Also can act on sphingosylphosphphorylcholine 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. Tumor cell motility-stimulating factor.<ref>PMID:11559573</ref> <ref>PMID:1733949</ref> <ref>PMID:21240271</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 5mhp" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Ectonucleotide pyrophosphatase/phosphodiesterase 3D structures|Ectonucleotide pyrophosphatase/phosphodiesterase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Alkylglycerophosphoethanolamine phosphodiesterase]]
+[[Category: Homo sapiens]]
-[[Category: Fleury, D]]
+[[Category: Large Structures]]
-[[Category: Lamers, M]]
+[[Category: Fleury D]]
-[[Category: Mollat, P]]
+[[Category: Lamers M]]
-[[Category: Mueller, I]]
+[[Category: Mollat P]]
-[[Category: Triballeau, N]]
+[[Category: Mueller I]]
-[[Category: Vercheval, L]]
+[[Category: Triballeau N]]
-[[Category: Atx]]
+[[Category: Vercheval L]]
-[[Category: Enpp2]]
-[[Category: Hydrolase]]
-[[Category: Inhibitor]]

5mhp

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Current revision

Novel Imidazo[1,2-a]pyridine Derivatives with Potent Autotaxin/ENPP2 Inhibitor Activity

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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