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

31 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.

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.6b01743

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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

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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.",

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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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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

PY - 2017/3/9

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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

ASJC Scopus subject areas

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