Rational design of autotaxin inhibitors by structural evolution of endogenous modulators

Keune, Willem-Jan and Potjewyd, Frances and Heidebrecht, Tatjana and Salgado-Polo, Fernando and Macdonald, Simon J. F. and Chelvarajan, Lakshman and Abdel Latif, Ahmed and Soman, Sony and Morris, Andrew J. and Watson, Allan J. B. and Jamieson, Craig and Perrakis, Anastassis (2017) Rational design of autotaxin inhibitors by structural evolution of endogenous modulators. Journal of Medicinal Chemistry, 60 (5). pp. 2006-2017. ISSN 0022-2623 (https://doi.org/10.1021/acs.jmedchem.6b01743)

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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.


Keune, Willem-Jan, Potjewyd, Frances ORCID logoORCID: https://orcid.org/0000-0003-4241-9873, Heidebrecht, Tatjana, Salgado-Polo, Fernando, Macdonald, Simon J. F., Chelvarajan, Lakshman, Abdel Latif, Ahmed, Soman, Sony, Morris, Andrew J., Watson, Allan J. B., Jamieson, Craig ORCID logoORCID: https://orcid.org/0000-0002-6567-8272 and Perrakis, Anastassis;