5M7M

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

Summary for 5M7M

• Entry DOI: 10.2210/pdb5m7m/pdb
• Descriptor: Ectonucleotide pyrophosphatase/phosphodiesterase family member 2, ZINC ION, alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (11 entities in total)
• Functional Keywords: atx, inhibitor, enpp2, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted : Q13822
• Total number of polymer chains: 1
• Total formula weight: 102843.92

Authors

Wolhkoning, A.,Fleury, D.,Leonard, P.,Triballeau, N.,Mollat, P.,Vercheval, L. (deposition date: 2016-10-28, release date: 2017-08-30, Last modification date: 2024-10-23)

Primary citation

Joncour, A.,Desroy, N.,Housseman, C.,Bock, X.,Bienvenu, N.,Cherel, L.,Labeguere, V.,Peixoto, C.,Annoot, D.,Lepissier, L.,Heiermann, J.,Hengeveld, W.J.,Pilzak, G.,Monjardet, A.,Wakselman, E.,Roncoroni, V.,Le Tallec, S.,Galien, R.,David, C.,Vandervoort, N.,Christophe, T.,Conrath, K.,Jans, M.,Wohlkonig, A.,Soror, S.,Steyaert, J.,Touitou, R.,Fleury, D.,Vercheval, L.,Mollat, P.,Triballeau, N.,van der Aar, E.,Brys, R.,Heckmann, B.
Discovery, Structure-Activity Relationship, and Binding Mode of an Imidazo[1,2-a]pyridine Series of Autotaxin Inhibitors.
J. Med. Chem., 60:7371-7392, 2017

PubMed Abstract: Autotaxin (ATX) is a secreted enzyme playing a major role in the production of lysophosphatidic acid (LPA) in blood through hydrolysis of lysophosphatidyl choline (LPC). The ATX-LPA signaling axis arouses a high interest in the drug discovery industry as it has been implicated in several diseases including cancer, fibrotic diseases, and inflammation, among others. An imidazo[1,2-a]pyridine series of ATX inhibitors was identified out of a high-throughput screening (HTS). A cocrystal structure with one of these compounds and ATX revealed a novel binding mode with occupancy of the hydrophobic pocket and channel of ATX but no interaction with zinc ions of the catalytic site. Exploration of the structure-activity relationship led to compounds displaying high activity in biochemical and plasma assays, exemplified by compound 40. Compound 40 was also able to decrease the plasma LPA levels upon oral administration to rats.

PubMed: 28731719
DOI: 10.1021/acs.jmedchem.7b00647

Experimental method

X-RAY DIFFRACTION (2.7 Å)