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

Internal Medicine

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

34 Scopus citations

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 signaling 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
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01743
State	Published - Mar 9 2017

Bibliographical note

Publisher Copyright:
© 2017 American Chemical Society.

Funding

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. High resolution mass spectral data was obtained at the EPSRC Mass Spectrometry facility at the University of Swansea, UK.

Funders	Funder number
EPRSC	EP/L505080/1
University of Kentucky teams
National Institutes of Health (NIH)	1R01HL120507, BX001984-01
National Institutes of Health (NIH)
U.S. Department of Defense	BC150305P1
U.S. Department of Defense
NIH Office of the Director	S10OD021753
NIH Office of the Director
GlaxoSmithKline
Engineering and Physical Sciences Research Council
Scottish Funding Council, United Kingdom
Swansea University
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	700.10.354
Nederlandse Organisatie voor Wetenschappelijk Onderzoek

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.6b01743

Cite this

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

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Keune, WJ, 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

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AU - Macdonald, Simon J.F.

AU - Chelvarajan, Lakshman

AU - Abdel Latif, Ahmed

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AU - Perrakis, Anastassis

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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 signaling in cells and reduces LPA synthesis in vivo, providing a promising natural product derived scaffold for drug discovery.

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Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

Access to Document

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