Discovery of potent inhibitors of the lyso phospholipase autotaxin

Shah, Pritom; Cheasty, Anne; Foxton, Caroline; Raynham, Tony; Farooq, Muddasar; Gutierrez, Irene Farre; Lejeune, Aurore; Pritchard, Michelle; Turnbull, A.P.; Pang, Leon; Owen, Paul; Boyd, Susan M.; Stowell, Alexandra; Jordan, Allan M.; Hamilton, Niall M.; Hitchin, James R.; Stockley, Martin L.; MacDonald, Ellen; Quesada, Mar Jimenez; Trivier, Elisabeth; Skeete, Jana; Ovaa, Huib; Moolenaar, Wouter H.; Ryder, Hamish

doi:10.1016/j.bmcl.2016.10.036

Cited by 27 publications

(35 citation statements)

References 19 publications

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“…2D-F). TILs migration could be rescued by incubating melanoma media with unrelated small-molecule ATX inhibitors, namely PF-8380 (Gierse et al, 2010) and IOA-289 (formerly CRT750; (Shah et al, 2016)) ( Fig. 2G).…”

Section: Melanoma Tils Constitute a Heterogeneous Population Of T Celmentioning

confidence: 99%

Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8⁺T cells

Matas-Rico

Àvila

Zon

et al. 2020

Preprint

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To improve immunotherapy efficacy, a better understanding of the factors that regulate Tcell migration into tumors is essential. Here we uncover a role for autotaxin (ATX) in this process. ATX (encoded by ENPP2) produces lysophosphatidic acid (LPA) that activates G protein-coupled receptors (LPAR1-6) to regulate multiple (patho)physiological processes, including tumor progression via LPAR1 and lymphocyte homing via LPAR2.Unexpectedly, we find that melanoma cell-secreted ATX is a major chemorepellent for tumor-infiltrating lymphocytes ex vivo through Gα12/13-coupled LPAR6, with ATX functioning as an LPA-producing chaperone. Using an anti-cancer vaccination model, we provide proof-of-concept that secreted ATX opposes tumor infiltration of CD8+ T cells.Additionally, ENPP2 expression in melanoma tumors correlates with reduced CD8+ T-cell infiltration as inferred from single-cell transcriptomics. Hence, by counteracting T-cell infiltration while activating tumor cells via different LPA receptors, the ATX/LPA complex exerts dual actions in the tumor immune microenvironment, which may provide new therapeutic approaches.

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Section: Melanoma Tils Constitute a Heterogeneous Population Of T Celmentioning

confidence: 99%

Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8⁺T cells

Matas-Rico

Àvila

Zon

et al. 2020

Preprint

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“…3, Figure 1). By contrast, a recent series of indole-based ATX inhibitors 7 and the lead compound of an independent discovery program 8 are reported to occupy the hydrophobic pocket and tunnel, without interacting with the hydrophilic groove or the active site, acting as allosteric inhibitors, similar to natural bile salts.…”

Section: Introductionmentioning

confidence: 99%

Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators

et al. 2017

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This version is available at https://strathprints.strath.ac.uk/59722/ Strathprints is designed to allow users to access the research output of the University of Strathclyde. Unless otherwise explicitly stated on the manuscript, Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Please check the manuscript for details of any other licences that may have been applied. You may not engage in further distribution of the material for any profitmaking activities or any commercial gain. You may freely distribute both the url (https://strathprints.strath.ac.uk/) and the content of this paper for research or private study, educational, or not-for-profit purposes without prior permission or charge.Any correspondence concerning this service should be sent to the Strathprints administrator: strathprints@strath.ac.ukThe Strathprints institutional repository (https://strathprints.strath.ac.uk) is a digital archive of University of Strathclyde research outputs. It has been developed to disseminate open access research outputs, expose data about those outputs, and enable the management and persistent access to Strathclyde's intellectual output. Rational design of Autotaxin inhibitors by structural evolution of endogenous modulatorsWillem-Jan Keune, † Frances Potjewyd, Tatjana AbstractAutotaxin 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.

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“…The structural characterization of the ATX tripartite site (Fig.1A-B) has created a remarkable potential for selective inhibitor design (14)(15)(16)) that includes lipid-based inhibitors (17), DNA aptamers (18) and small molecules. The latter can be classified in four distinct types depending on their binding modes to the tripartite site (19) (Fig.1C).…”

Section: Introductionmentioning

confidence: 99%

Lysophosphatidic acid produced by autotaxin acts as an allosteric modulator of its catalytic efficiency

Salgado-Polo

Fish

Matsoukas

et al. 2018

Journal of Biological Chemistry

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Autotaxin is a secreted glycoprotein and the only member of the ectonucleotide pyrophosphatase/phosphodiesterase family that converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). LPA controls key responses such as cell migration, proliferation, and survival, implicating ATX-LPA signalling in various (patho)physiological processes and establishing it as a drug target. ATX structural and functional studies have revealed an orthosteric and an allosteric site, called the "pocket" and the "tunnel," respectively. However, the mechanisms in allosteric modulation of ATX's activity as a lysophospholipase D are unclear. Here, using the physiological LPC substrate, a new fluorescent substrate, and diverse ATX inhibitors, we revisited the kinetics and allosteric regulation of the ATX catalytic cycle, dissecting the different steps and pathways leading to LPC hydrolysis. We found that ATX activity is stimulated by LPA and that LPA activates ATX lysophospholipase D activity by binding to the ATX tunnel. A consolidation of all experimental kinetics data yielded a comprehensive catalytic model supported by molecular modelling simulations, and suggested a positive feedback mechanism that is regulated by the abundance of the LPA products activating hydrolysis of different LPC species. Our results complement and extend the current understanding of ATX hydrolysis in light of the allosteric regulation by ATX-produced LPA species, and have implications for the design and application of both orthosteric and allosteric ATX inhibitors.Autotaxin (ATX or ENPP2) is a secreted glycoprotein and a unique member of the ectonucleotide pyrophosphatase / phosphordiesterase (ENPP) family (1). It is the only ENPP family member with lysophospholipase D (lysoPLD) activity (EC 3.1.4.39), and it is the main enzyme responsible for the hydrolysis of lysophosphatidylcholine (2-acyl-sn-glycero-3-phosphocholine or LPC) to produce the bioactive lipid lysophosphatidic acid (monoacyl-snglycerol-3-phosphate or LPA) (2-4). LPA acts as a ligand for several LPA receptors (LPARs) showing overlapping activities. The ATX-LPA signalling axis is vital for embryonic development and has been implicated in many (patho)physiological processes, which include vascular development (5), cancer metastasis (6), and other human diseases, such as fibrosis (7) and cholestatic pruritus (8). ATX is translated as a preproenzyme that is secreted to plasma upon its proteolytic processing, resulting in its native structural domains (9, 10). Close to the Nterminus, ATX presents two somatomedin B (SMB)-like domains, which are followed by the central catalytic phosphodiesterase (PDE) domain, and an inactive nuclease-like domain. Catalysis occurs in a bimetallic active site presenting two Zn 2+ atoms, and resembles that of other members of the alkaline phosphatase family (11). The catalytic site of ATX is organized in a tripartite binding site (Fig.1), where the active site is followed by a shallow hydrophilic groove that (11)(12)(13), and a tunnel, also called ...

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Discovery of potent inhibitors of the lyso phospholipase autotaxin

Cited by 27 publications

References 19 publications

Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8⁺T cells

Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8⁺T cells

Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators

Lysophosphatidic acid produced by autotaxin acts as an allosteric modulator of its catalytic efficiency

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Discovery of potent inhibitors of the lyso phospholipase autotaxin

Cited by 27 publications

References 19 publications

Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+T cells

Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+T cells

Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators

Lysophosphatidic acid produced by autotaxin acts as an allosteric modulator of its catalytic efficiency

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Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8⁺T cells

Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8⁺T cells