Development of Autotaxin Inhibitors: An Overview of the Patent and Primary Literature

Castagna, Diana; Budd, David C.; Macdonald, Simon J. F.; Jamieson, Craig; Watson, Allan J. B.

doi:10.1021/acs.jmedchem.5b01599

Cited by 62 publications

(86 citation statements)

References 74 publications

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“…Some attempts have been made towards the development of small‐molecule inhibitors of autotaxin, one of which has entered clinical trials . Based on a recent high‐throughput and in silico screening study compound 52 (Figure ) was identified as a potent autotaxin inhibitor with an IC 50 of 117 nM .…”

Section: Pharmacological Activity Of Morpholine Derivatives On Varioumentioning

confidence: 99%

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Kourounakis

Xanthopoulos

Tzara

2019

Medicinal Research Reviews

171

114

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Morpholine is a heterocycle featured in numerous approved and experimental drugs as well as bioactive molecules. It is often employed in the field of medicinal chemistry for its advantageous physicochemical, biological, and metabolic properties, as well as its facile synthetic routes. The morpholine ring is a versatile and readily accessible synthetic building block, it is easily introduced as an amine reagent or can be built according to a variety of available synthetic methodologies. This versatile scaffold, appropriately substituted, possesses a wide range of biological activities. There are many examples of molecular targets of morpholine bioactive in which the significant contribution of the morpholine moiety has been demonstrated; it is an integral component of the pharmacophore for certain enzyme active‐site inhibitors whereas it bestows selective affinity for a wide range of receptors. A large body of in vivo studies has demonstrated morpholine's potential to not only increase potency but also provide compounds with desirable drug‐like properties and improved pharamacokinetics. In this review we describe the medicinal chemistry/pharmacological activity of morpholine derivatives on various therapeutically related molecular targets, attempting to highlight the importance of the morpholine ring in drug design and development as well as to justify its classification as a privileged structure.

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Section: Pharmacological Activity Of Morpholine Derivatives On Varioumentioning

confidence: 99%

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Kourounakis

Xanthopoulos

Tzara

2019

Medicinal Research Reviews

171

114

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“…The effect of rodent genetic background on weight loss and inflammation associated with ATX deletion obviously needs further investigation, given the broad genetic diversity among humans. In theory, weight loss induced by ATX deletion could potentially be a concern in the development of ATX inhibitors for the treatment of chronic diseases (45). However, it is unlikely that chemical inhibitors achieve .95% inhibition of ATX activity, which, by inference, is associated with the weight loss observed in the current study.…”

Section: Discussionmentioning

confidence: 72%

Autotaxin determines colitis severity in mice and is secreted by B cells in the colon

et al. 2018

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Autotaxin (ATX or ENPP2) is a secreted lysophospholipase D that produces lysophosphatidic acid (LPA), a pleiotropic lipid mediator acting on specific GPCRs. ATX and LPA have been implicated in key (patho)physiologic processes, including embryonic development, lymphocyte homing, inflammation, and cancer progression. Using LPA receptor knockout mice, we previously uncovered a role for LPA signaling in promoting colitis and colorectal cancer. Here, we examined the role of ATX in experimental colitis through inducible deletion of Enpp2 in adult mice. ATX expression was increased upon induction of colitis, whereas ATX deletion reduced the severity of inflammation in both acute and chronic colitis, accompanied by transient weight loss. ATX expression in lymphocytes was strongly reduced in Rag1−/− and µMT mice, suggesting B cells as a major ATX‐producing source, which was validated by immunofluorescence and biochemical analyses. ATX secretion by B cells from control, but not Enpp2 knockout, mice led to ERK activation in colorectal cancer cells and promoted T cell migration. We conclude that ATX deletion suppresses experimental colitis and that B cells are a major source of ATX in the colon. Our study suggests that pharmacological inhibition of ATX could be a therapeutic strategy in colitis.—Lin, S., Haque, A., Raeman, R., Guo, L., He, P., Denning, T. L., El‐Rayes, B., Moolenaar, W. H., Yun, C. C. Autotaxin determines colitis severity in mice and is secreted by B cells in the colon. FASEB J. 33, 3623–3635 (2019). http://www.fasebj.org

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“…Activity-based lead discovery campaigns, using artificial substrates as activity reporters, subsequently made important contributions, many of which are reviewed in e.g. [35,36]. The structural characterization of rat and mouse ATX structures in 2011 [24,26], enabled a remarkable potential for selective inhibitor design by focusing on the three dimensional architecture of the ATX active site.…”

Section: The Autotaxin Inhibitor Familymentioning

confidence: 99%

The potential of different Autotaxin inhibitor types regulating catalysis-dependent and -independent signalling

F¹,

Perrakis²

2019

Preprint

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Autotaxin (ATX) is a secreted lysophospholipase D, catalysing the conversion of lysophosphatidylcholine (LPC) to bioactive lysophosphatidic acid (LPA). LPA acts through two families of G protein-coupled receptors (GPCRs) controlling key cellular responses, and is implicated in many physiological processes and pathologies. ATX has therefore been established as an important drug target in the pharmaceutical industry. Structural and biochemical studies of ATX have shown that it has a bimetallic nucleophilic catalytic site, a substrate-binding (orthosteric) hydrophobic pocket that accommodates the lipid alkyl chain, and an allosteric tunnel that can accommodate various steroids and LPA. Here we first review what is known about ATX-mediated catalysis, crucially in light of allosteric regulation. We then present the known ATX catalysis-independent functions, including binding to cell-surface integrins and proteoglycans. In light of these data we then discuss the four types of ATX inhibitors, as classified depending on their binding to the orthosteric and/or the allosteric site. Finally, we analyse the binding mode of known members of all four types and discuss how mechanistic differences might differentially modulate the activity of the ATX-LPA signalling axis, and clinical applications including cancer.

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Development of Autotaxin Inhibitors: An Overview of the Patent and Primary Literature

Cited by 62 publications

References 74 publications

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Autotaxin determines colitis severity in mice and is secreted by B cells in the colon

The potential of different Autotaxin inhibitor types regulating catalysis-dependent and -independent signalling

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