Rational design of autotaxin inhibitors by structural evolution of endogenous modulators

Willem-Jan Keune; Frances Potjewyd; Tatjana Heidebrecht; Fernando Salgado-Polo; Simon J. F. Macdonald; Lakshman Chelvarajan; Ahmed Abdel Latif; Sony Soman; Andrew J. Morris; Allan J. B. Watson; Craig Jamieson; Anastassis Perrakis

doi:10.1021/acs.jmedchem.6b01743

Rational design of autotaxin inhibitors by structural evolution of endogenous modulators

Willem-Jan Keune, Frances Potjewyd, Tatjana Heidebrecht, Fernando Salgado-Polo, Simon J. F. Macdonald, Lakshman Chelvarajan, Ahmed Abdel Latif, Sony Soman, Andrew J. Morris, Allan J. B. Watson, Craig Jamieson, Anastassis Perrakis

School of Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

Autotaxin produces the bioactive lipid lysophosphatidic acid (LPA), and is a drug target of considerable interest for numerous pathologies. We report the expedient, structure-guided evolution of weak physiological allosteric inhibitors (bile salts) into potent competitive Autotaxin inhibitors that do not interact with the catalytic site. Functional data confirms that our lead compound attenuates LPA mediated signalling in cells, and reduces LPA synthesis in vivo, providing a promising natural product derived scaffold for drug discovery.

Original language	English
Pages (from-to)	2006-2017
Number of pages	12
Journal	Journal of Medicinal Chemistry
Volume	60
Issue number	5
Early online date	6 Feb 2017
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01743
Publication status	Published - 9 Mar 2017

Keywords

Lipid lysophosphatidic acid
Autotaxin
Allosteric inhibitors
Scaffolds
Drug discovery
Catalytic site
Cell signalling

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10.1021/acs.jmedchem.6b01743

https://strathprints.strath.ac.uk/id/eprint/59722

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Keune, W.-J., Potjewyd, F., Heidebrecht, T., Salgado-Polo, F., Macdonald, S. J. F., Chelvarajan, L., Abdel Latif, A., Soman, S., Morris, A. J., Watson, A. J. B., Jamieson, C., & Perrakis, A. (2017). Rational design of autotaxin inhibitors by structural evolution of endogenous modulators. Journal of Medicinal Chemistry, 60(5), 2006-2017. https://doi.org/10.1021/acs.jmedchem.6b01743

@article{275e7ed075fc45a5bdcbdf49315852a4,

title = "Rational design of autotaxin inhibitors by structural evolution of endogenous modulators",

abstract = "Autotaxin produces the bioactive lipid lysophosphatidic acid (LPA), and is a drug target of considerable interest for numerous pathologies. We report the expedient, structure-guided evolution of weak physiological allosteric inhibitors (bile salts) into potent competitive Autotaxin inhibitors that do not interact with the catalytic site. Functional data confirms that our lead compound attenuates LPA mediated signalling in cells, and reduces LPA synthesis in vivo, providing a promising natural product derived scaffold for drug discovery.",

keywords = "Lipid lysophosphatidic acid, Autotaxin, Allosteric inhibitors, Scaffolds, Drug discovery, Catalytic site, Cell signalling",

author = "Willem-Jan Keune and Frances Potjewyd and Tatjana Heidebrecht and Fernando Salgado-Polo and Macdonald, {Simon J. F.} and Lakshman Chelvarajan and {Abdel Latif}, Ahmed and Sony Soman and Morris, {Andrew J.} and Watson, {Allan J. B.} and Craig Jamieson and Anastassis Perrakis",

note = "For financial support we thank: NWO for supporting work on Autotaxin (700.10.354) for support to the lab of A.P.; GlaxoSmithKline, EPRSC (EP/L505080/1), and Scottish Funding Council for a Ph.D. studentship for F.P.; NIH (1R01HL120507), VA (BX001984-01), and DOD (BC150305P1) for support to the University of Kentucky teams.",

year = "2017",

month = mar,

day = "9",

doi = "10.1021/acs.jmedchem.6b01743",

language = "English",

volume = "60",

pages = "2006--2017",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society (ACS)",

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Keune, W-J, Potjewyd, F, Heidebrecht, T, Salgado-Polo, F, Macdonald, SJF, Chelvarajan, L, Abdel Latif, A, Soman, S, Morris, AJ, Watson, AJB, Jamieson, C & Perrakis, A 2017, 'Rational design of autotaxin inhibitors by structural evolution of endogenous modulators', Journal of Medicinal Chemistry, vol. 60, no. 5, pp. 2006-2017. https://doi.org/10.1021/acs.jmedchem.6b01743

TY - JOUR

T1 - Rational design of autotaxin inhibitors by structural evolution of endogenous modulators

AU - Keune, Willem-Jan

AU - Potjewyd, Frances

AU - Heidebrecht, Tatjana

AU - Salgado-Polo, Fernando

AU - Macdonald, Simon J. F.

AU - Chelvarajan, Lakshman

AU - Abdel Latif, Ahmed

AU - Soman, Sony

AU - Morris, Andrew J.

AU - Watson, Allan J. B.

AU - Jamieson, Craig

AU - Perrakis, Anastassis

N1 - For financial support we thank: NWO for supporting work on Autotaxin (700.10.354) for support to the lab of A.P.; GlaxoSmithKline, EPRSC (EP/L505080/1), and Scottish Funding Council for a Ph.D. studentship for F.P.; NIH (1R01HL120507), VA (BX001984-01), and DOD (BC150305P1) for support to the University of Kentucky teams.

PY - 2017/3/9

Y1 - 2017/3/9

N2 - Autotaxin produces the bioactive lipid lysophosphatidic acid (LPA), and is a drug target of considerable interest for numerous pathologies. We report the expedient, structure-guided evolution of weak physiological allosteric inhibitors (bile salts) into potent competitive Autotaxin inhibitors that do not interact with the catalytic site. Functional data confirms that our lead compound attenuates LPA mediated signalling in cells, and reduces LPA synthesis in vivo, providing a promising natural product derived scaffold for drug discovery.

AB - Autotaxin produces the bioactive lipid lysophosphatidic acid (LPA), and is a drug target of considerable interest for numerous pathologies. We report the expedient, structure-guided evolution of weak physiological allosteric inhibitors (bile salts) into potent competitive Autotaxin inhibitors that do not interact with the catalytic site. Functional data confirms that our lead compound attenuates LPA mediated signalling in cells, and reduces LPA synthesis in vivo, providing a promising natural product derived scaffold for drug discovery.

KW - Lipid lysophosphatidic acid

KW - Autotaxin

KW - Allosteric inhibitors

KW - Scaffolds

KW - Drug discovery

KW - Catalytic site

KW - Cell signalling

U2 - 10.1021/acs.jmedchem.6b01743

DO - 10.1021/acs.jmedchem.6b01743

M3 - Article

SN - 0022-2623

VL - 60

SP - 2006

EP - 2017

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 5

ER -

Rational design of autotaxin inhibitors by structural evolution of endogenous modulators

Abstract

Keywords

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