PF‐8380 and Closely Related Analogs: Synthesis and Structure–Activity Relationship towards Autotaxin Inhibition and Glioma Cell Viability

St-Coeur, Patrick-Denis; Ferguson, Dean; Morin, Pier Jr; Touaibia, Mohamed

doi:10.1002/ardp.201200395

Cited by 28 publications

(29 citation statements)

References 40 publications

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“…These findings are consistent with SAR previously established for the hydrophobic pocket, all of which indicate a degree of lipophilicity in this region is required for adequate levels of ATX-inhibitory activity. [10][11][12][13] In this initial survey of SAR, we also sought to examine the length and nature of the linker (5-7). While the piperazine unit in 4 was optimal, linear systems exhibit only slightly lower potency (5-6); however, a very short spacer (7) resulted in no detectable inhibitory activity.…”

Section: Figure 2 Overarching Design Hypothesismentioning

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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Section: Figure 2 Overarching Design Hypothesismentioning

confidence: 99%

Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators

et al. 2017

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“…At the present time there is no approved ATX inhibitor available for therapy; however, development of ATX inhibitors has gained increasing interest with several smallmolecule ATX inhibitors having been described (Ferry et al, 2008;Saunders et al, 2008;Albers et al, 2010;Gierse et al, 2010;Hoeglund et al, 2010;Mize et al, 2011;Gotoh et al, 2012;Kawaguchi et al, 2013;St-Coeur et al, 2013). A considerable amount of effort has been devoted to the characterization of inhibitors that interact with the active site of ATX.…”

Section: Introductionmentioning

confidence: 99%

Hits of a High-Throughput Screen Identify the Hydrophobic Pocket of Autotaxin/Lysophospholipase D As an Inhibitory Surface

et al. 2013

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Autotaxin (ATX), a lysophospholipase D, plays an important role in cancer invasion, metastasis, tumor progression, tumorigenesis, neuropathic pain, fibrotic diseases, cholestatic pruritus, lymphocyte homing, and thrombotic diseases by producing the lipid mediator lysophosphatidic acid (LPA). A high-throughput screen of ATX inhibition using the lysophosphatidylcholine-like substrate fluorogenic substrate 3 (FS-3) and ∼10,000 compounds from the University of Cincinnati Drug Discovery Center identified several small-molecule inhibitors with IC 50 vales ranging from nanomolar to low micromolar. The pharmacology of the three most potent compounds: 918013 (1; 2,4-dichloro-N-(3-fluorophenyl)-5-(4-morpholinylsulfonyl) benzamide), 931126 (2; 4-oxo-4-{2-[(5-phenoxy-1H-indol-2-yl)carbonyl]hydrazino}-N-(4-phenylbutan-2-yl)butanamide), and 966791 (3; N-(2,6-dimethylphenyl)-2-[N-(2-furylmethyl)(4-(1,2,3,4-tetraazolyl)phenyl)carbonylamino]-2-(4-hydroxy-3-methoxyphenyl) acetamide), were further characterized in enzyme, cellular, and whole animal models. Compounds 1 and 2 were competitive inhibitors of ATX-mediated hydrolysis of the lysophospholipase substrate FS-3. In contrast, compound 3 was a competitive inhibitor of both FS-3 and the phosphodiesterase substrate p-nitrophenyl thymidine 59-monophosphate. Computational docking and mutagenesis suggested that compounds 1 and 2 target the hydrophobic pocket, thereby blocking access to the active site of ATX. The potencies of compounds 1-3 were comparable to each other in each of the assays. All of these compounds significantly reduced invasion of A2058 human melanoma cells in vitro and the colonization of lung metastases by B16-F10 murine melanoma cells in C57BL/6 mice. The compounds had no agonist or antagonist effects on select LPA or sphingosine 1-phosphate receptors, nor did they inhibit nucleotide pyrophosphatase/phosphodiesterase (NPP) enzymes NPP6 and NPP7. These results identify the molecular surface of the hydrophobic pocket of ATX as a targetbinding site for inhibitors of enzymatic activity.

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“…A structure-activity relationship study of PF-8380 also showed the importance of a 3,5-dichloroaromatic ring, but this study also did not use a substituted phenoxy ring. [60] Only one of the analogs with the nitro group ortho to the piperazine ring ( 11 , IC 50 3 μM) and two ortho carboxy analogs ( 42 , IC 50 1.8 μM and 44 , IC 50 2.2 μM) showed improved potency over the lead, indicating ortho substitution on the phenyl piperazine ring may not lead to further improvement. A similar trend was seen with boronic acid substitution on an aromatic ring by Albers et al (figure 6), where Albers 74 (IC 50 > 5 μM) was far less potent than Albers 72 or 73 (IC 50 28 nM and 5.7 nM, respectively) when monitoring choline release from the natural substrate, LPC.…”

Section: Discussionmentioning

confidence: 99%

“…This may suggest that, like PF8380 and Hoeglund 5, having a dichloro substitution may improve potency, as also seen during structure-activity relationship studies of PF8380. [60] Across the 66 compounds tested, minor changes in structure caused vast differences in biological activity. These drastic changes are activity cliffs, as described by both Dimova et al and Hu et al .…”

Section: Discussionmentioning

confidence: 99%

Discovery and synthetic optimization of a novel scaffold for hydrophobic tunnel-targeted autotaxin inhibition

Ragle

Palanisamy

Joe

et al. 2016

Bioorganic & Medicinal Chemistry

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Autotaxin (ATX) is a ubiquitous ectoenzyme that hydrolyzes lysophosphatidylcholine (LPC) to form the bioactive lipid mediator lysophosphatidic acid (LPA). LPA activates specific G-protein coupled receptors to elicit downstream effects leading to cellular motility, survival, and invasion. Through these pathways, upregulation of ATX is linked to diseases such as cancer and cardiovascular disease. Recent crystal structures confirm that the catalytic domain of ATX contains multiple binding regions including a polar active site, hydrophobic tunnel, and a hydrophobic pocket. This finding is consistent with the promiscuous nature of ATX hydrolysis of multiple and diverse substrates and prior investigations of inhibitor impacts on ATX enzyme kinetics. The current study used virtual screening methods to guide experimental identification and characterization of inhibitors targeting the hydrophobic region of ATX. An initially discovered inhibitor, GRI392104 (IC50 4 μM) was used as a lead for synthetic optimization. In total twelve newly synthesized inhibitors of ATX were more potent than GRI392104 and were selective for ATX as they had no effect on other LPC-specific NPP family members or on LPA1–5 GPCR.

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PF‐8380 and Closely Related Analogs: Synthesis and Structure–Activity Relationship towards Autotaxin Inhibition and Glioma Cell Viability

Cited by 28 publications

References 40 publications

Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators

Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators

Hits of a High-Throughput Screen Identify the Hydrophobic Pocket of Autotaxin/Lysophospholipase D As an Inhibitory Surface

Discovery and synthetic optimization of a novel scaffold for hydrophobic tunnel-targeted autotaxin inhibition

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