5olb | pdb_00005olb
crystal structure of autotaxin in complex with PF-8380
Structural highlights
DiseaseENPP2_MOUSE Note=May contribute to obesity. FunctionENPP2_MOUSE 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 PubMedIn an effort to find new therapeutic interventions addressing the unmet medical need of patients with idiopathic pulmonary fibrosis, we initiated a program to identify new autotaxin (ATX) inhibitors. Starting from a recently published compound (PF-8380), we identified several highly potent ATX inhibitors with improved pharmacokinetic and safety profiles. Further optimization efforts resulted in the identification of a single-digit nanomolar lead compound (BI-2545) that shows substantial lowering of LPA in vivo and is therefore considered a valuable tool for further studies. Discovery of BI-2545: A Novel Autotaxin Inhibitor That Significantly Reduces LPA Levels in Vivo.,Kuttruff CA, Ferrara M, Bretschneider T, Hoerer S, Handschuh S, Nosse B, Romig H, Nicklin P, Roth GJ ACS Med Chem Lett. 2017 Nov 8;8(12):1252-1257. doi:, 10.1021/acsmedchemlett.7b00312. eCollection 2017 Dec 14. PMID:29259743[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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