title: Discovery of potent inhibitors of the lysophospholipase autotaxin.
abstract: The autotaxin-lysophosphatidic acid (ATX-LPA) axis has been implicated in several disease conditions including inflammation, fibrosis and cancer. This makes ATX an attractive drug target and its inhibition may lead to useful therapeutic agents. Through a high throughput screen (HTS) we identified a series of small molecule inhibitors of ATX which have subsequently been optimized for potency, selectivity and developability properties. This has delivered drug-like compounds such as 9v (CRT0273750) which modulate LPA levels in plasma and are suitable for in vivo studies. X-ray crystallography has revealed that these compounds have an unexpected binding mode in that they do not interact with the active site zinc ions but instead occupy the hydrophobic LPC pocket extending from the active site of ATX together with occupying the LPA 'exit' channel.
authors: Cancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors: Pritom
authors: P
authors: Shah
authors: Cancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors: Anne
authors: A
authors: Cheasty
authors: Cancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors: Caroline
authors: C
authors: Foxton
authors: Cancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors: Tony
authors: T
authors: Raynham
authors: Cancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors: Muddasar
authors: M
authors: Farooq
authors: Cancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors: Irene Farre
authors: IF
authors: Gutierrez
authors: Cancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors: Aurore
authors: A
authors: Lejeune
authors: Cancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors: Michelle
authors: M
authors: Pritchard
authors: Cancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors: Andrew
authors: A
authors: Turnbull
authors: Cancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors: Leon
authors: L
authors: Pang
authors: Cancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors: Paul
authors: P
authors: Owen
authors: Cancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors: Susan
authors: S
authors: Boyd
authors: Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors: Alexandra
authors: A
authors: Stowell
authors: Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors: Allan
authors: A
authors: Jordan
authors: Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors: Niall M
authors: NM
authors: Hamilton
authors: Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors: James R
authors: JR
authors: Hitchin
authors: Cancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors: Martin
authors: M
authors: Stockley
authors: Cancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors: Ellen
authors: E
authors: MacDonald
authors: Cancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors: Mar Jimenez
authors: MJ
authors: Quesada
authors: Cancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors: Elisabeth
authors: E
authors: Trivier
authors: Cancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors: Jana
authors: J
authors: Skeete
authors: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors: Huib
authors: H
authors: Ovaa
authors: Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors: Wouter H
authors: WH
authors: Moolenaar
authors: Cancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors: Hamish
authors: H
authors: Ryder
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008245:Lysophospholipase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000099189:Lysophospholipase D
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008245:Lysophospholipase; D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D011725:Pyridines; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid
keywords: Autotaxin (ATX); Cancer; Lysophosphatidic acid (LPA); Lysophosphatidylcholine (LPC)