Structure-activity relationships of small molecule autotaxin inhibitors with a discrete binding mode

Lisa M. Miller, Willem-Jan Keune, Diana Castagna, Louise C. Young, Emma L. Duffy, Frances Potjewyd, Fernando Salgado-Polo, Paloma Engel Garcia, Dima Semaan, John M. Pritchard, Anastassis Perrakis, Simon J. F. Macdonald, Craig Jamieson, Allan J. B. Watson

Research output: Contribution to journalArticle

11 Citations (Scopus)
38 Downloads (Pure)

Abstract

Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signalling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognized therapeutic target for a number of diseases including fibrotic diseases, cancer, and inflammation, amongst others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold. Herein, we report the structure-activity relationships (SAR) of a previously reported small molecule ATX inhibitor. We show through enzyme kinetics studies that analogues of this chemotype are noncompetitive inhibitors, and using a crystal structure with ATX we confirm the discrete binding mode.
Original languageEnglish
Pages (from-to)722-748
Number of pages27
JournalJournal of Medicinal Chemistry
Volume60
Issue number2
Early online date16 Dec 2016
DOIs
Publication statusPublished - 26 Jan 2017

Fingerprint

Structure-Activity Relationship
Lysophosphatidylcholines
Enzymes
Choline
Cell Movement
Cell Survival
Hydrolysis
Cell Proliferation
Ligands
Inflammation
Lipids
Neoplasms
lysophosphatidic acid
Therapeutics

Keywords

  • autotaxin
  • cell migration
  • lysophosphatidic acid
  • lysophosphatidylcholine
  • structure-activity relationships

Cite this

Miller, Lisa M. ; Keune, Willem-Jan ; Castagna, Diana ; Young, Louise C. ; Duffy, Emma L. ; Potjewyd, Frances ; Salgado-Polo, Fernando ; Garcia, Paloma Engel ; Semaan, Dima ; Pritchard, John M. ; Perrakis, Anastassis ; Macdonald, Simon J. F. ; Jamieson, Craig ; Watson, Allan J. B. / Structure-activity relationships of small molecule autotaxin inhibitors with a discrete binding mode. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 2. pp. 722-748.
@article{4ad77bc2179f42db9d6dd7b3c8b41fdf,
title = "Structure-activity relationships of small molecule autotaxin inhibitors with a discrete binding mode",
abstract = "Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signalling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognized therapeutic target for a number of diseases including fibrotic diseases, cancer, and inflammation, amongst others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold. Herein, we report the structure-activity relationships (SAR) of a previously reported small molecule ATX inhibitor. We show through enzyme kinetics studies that analogues of this chemotype are noncompetitive inhibitors, and using a crystal structure with ATX we confirm the discrete binding mode.",
keywords = "autotaxin, cell migration, lysophosphatidic acid, lysophosphatidylcholine, structure-activity relationships",
author = "Miller, {Lisa M.} and Willem-Jan Keune and Diana Castagna and Young, {Louise C.} and Duffy, {Emma L.} and Frances Potjewyd and Fernando Salgado-Polo and Garcia, {Paloma Engel} and Dima Semaan and Pritchard, {John M.} and Anastassis Perrakis and Macdonald, {Simon J. F.} and Craig Jamieson and Watson, {Allan J. B.}",
year = "2017",
month = "1",
day = "26",
doi = "10.1021/acs.jmedchem.6b01597",
language = "English",
volume = "60",
pages = "722--748",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "2",

}

Miller, LM, Keune, W-J, Castagna, D, Young, LC, Duffy, EL, Potjewyd, F, Salgado-Polo, F, Garcia, PE, Semaan, D, Pritchard, JM, Perrakis, A, Macdonald, SJF, Jamieson, C & Watson, AJB 2017, 'Structure-activity relationships of small molecule autotaxin inhibitors with a discrete binding mode', Journal of Medicinal Chemistry, vol. 60, no. 2, pp. 722-748. https://doi.org/10.1021/acs.jmedchem.6b01597

Structure-activity relationships of small molecule autotaxin inhibitors with a discrete binding mode. / Miller, Lisa M.; Keune, Willem-Jan; Castagna, Diana; Young, Louise C.; Duffy, Emma L.; Potjewyd, Frances; Salgado-Polo, Fernando; Garcia, Paloma Engel; Semaan, Dima; Pritchard, John M.; Perrakis, Anastassis; Macdonald, Simon J. F.; Jamieson, Craig; Watson, Allan J. B.

In: Journal of Medicinal Chemistry, Vol. 60, No. 2, 26.01.2017, p. 722-748.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Structure-activity relationships of small molecule autotaxin inhibitors with a discrete binding mode

AU - Miller, Lisa M.

AU - Keune, Willem-Jan

AU - Castagna, Diana

AU - Young, Louise C.

AU - Duffy, Emma L.

AU - Potjewyd, Frances

AU - Salgado-Polo, Fernando

AU - Garcia, Paloma Engel

AU - Semaan, Dima

AU - Pritchard, John M.

AU - Perrakis, Anastassis

AU - Macdonald, Simon J. F.

AU - Jamieson, Craig

AU - Watson, Allan J. B.

PY - 2017/1/26

Y1 - 2017/1/26

N2 - Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signalling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognized therapeutic target for a number of diseases including fibrotic diseases, cancer, and inflammation, amongst others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold. Herein, we report the structure-activity relationships (SAR) of a previously reported small molecule ATX inhibitor. We show through enzyme kinetics studies that analogues of this chemotype are noncompetitive inhibitors, and using a crystal structure with ATX we confirm the discrete binding mode.

AB - Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signalling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognized therapeutic target for a number of diseases including fibrotic diseases, cancer, and inflammation, amongst others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold. Herein, we report the structure-activity relationships (SAR) of a previously reported small molecule ATX inhibitor. We show through enzyme kinetics studies that analogues of this chemotype are noncompetitive inhibitors, and using a crystal structure with ATX we confirm the discrete binding mode.

KW - autotaxin

KW - cell migration

KW - lysophosphatidic acid

KW - lysophosphatidylcholine

KW - structure-activity relationships

UR - http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b01597

U2 - 10.1021/acs.jmedchem.6b01597

DO - 10.1021/acs.jmedchem.6b01597

M3 - Article

VL - 60

SP - 722

EP - 748

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 2

ER -