Characterization of non-lipid autotaxin inhibitors

Hoeglund, Adrienne B.; Howard, Angela L.; Wanjala, Irene W; Pham, Truc Chi T.; Parrill, Abby L.; Baker, Daniel L.

doi:10.1016/j.bmc.2009.11.056

Cited by 24 publications

(35 citation statements)

References 64 publications

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“…Thus, pharmacological inhibition of both ATX and LPA may serve as an effective method to reduce tumor vascularization. Since ATX is a member of the alkaline phosphatase superfamily of metalloenzymes, initial medicinal chemistry efforts focused on metal chelaters as ATX inhibitors (Hoeglund et al, 2010). The chelaters reduce the metal-ion stimulation of ATX activity by competing with active site histidine and aspartic acid residues for divalent metal ions (Clair et al, 2005;Hoeglund et al, 2010;Tokumura et al, 1998).…”

Section: Autotaxin and Lysophosphatidic Acid Signalingmentioning

confidence: 99%

“…Since ATX is a member of the alkaline phosphatase superfamily of metalloenzymes, initial medicinal chemistry efforts focused on metal chelaters as ATX inhibitors (Hoeglund et al, 2010). The chelaters reduce the metal-ion stimulation of ATX activity by competing with active site histidine and aspartic acid residues for divalent metal ions (Clair et al, 2005;Hoeglund et al, 2010;Tokumura et al, 1998). Not surprisingly, metal ion chelation is considered a relatively insensitive and non-specific method of ATX inhibition (Hoeglund et al, 2010).…”

Section: Autotaxin and Lysophosphatidic Acid Signalingmentioning

confidence: 99%

“…The chelaters reduce the metal-ion stimulation of ATX activity by competing with active site histidine and aspartic acid residues for divalent metal ions (Clair et al, 2005;Hoeglund et al, 2010;Tokumura et al, 1998). Not surprisingly, metal ion chelation is considered a relatively insensitive and non-specific method of ATX inhibition (Hoeglund et al, 2010). The library of ATX inhibitors has since expanded to include both non-lipid smallmolecule inhibitors as well as analogs of bioactive lipids.…”

Section: Autotaxin and Lysophosphatidic Acid Signalingmentioning

confidence: 99%

“…The library of ATX inhibitors has since expanded to include both non-lipid smallmolecule inhibitors as well as analogs of bioactive lipids. Both categories of drugs are promising in vitro, although the non-lipid ATX inhibitors are more compliant with the characteristic parameters often found in orally bioavailable drugs (Hoeglund et al, 2010;Keller et al, 2006). Furthermore, these non-lipid compounds exhibit enhanced specificity for ATX without affecting other members of the NPP family (Hoeglund et al, 2010).…”

Section: Autotaxin and Lysophosphatidic Acid Signalingmentioning

confidence: 99%

“…Both categories of drugs are promising in vitro, although the non-lipid ATX inhibitors are more compliant with the characteristic parameters often found in orally bioavailable drugs (Hoeglund et al, 2010;Keller et al, 2006). Furthermore, these non-lipid compounds exhibit enhanced specificity for ATX without affecting other members of the NPP family (Hoeglund et al, 2010). Despite the identification of new inhibitory agents, the lack of information regarding the threedimensional structure of ATX is impeding drug discovery .…”

Section: Autotaxin and Lysophosphatidic Acid Signalingmentioning

confidence: 99%

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New Molecular Targets for Anti-Angiogenic Therapeutic Strategies

Linkous¹,

Yazlovitskaya²

2012

Tumor Angiogenesis

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Section: Autotaxin and Lysophosphatidic Acid Signalingmentioning

confidence: 99%

Section: Autotaxin and Lysophosphatidic Acid Signalingmentioning

confidence: 99%

Section: Autotaxin and Lysophosphatidic Acid Signalingmentioning

confidence: 99%

Section: Autotaxin and Lysophosphatidic Acid Signalingmentioning

confidence: 99%

Section: Autotaxin and Lysophosphatidic Acid Signalingmentioning

confidence: 99%

See 3 more Smart Citations

New Molecular Targets for Anti-Angiogenic Therapeutic Strategies

Linkous¹,

Yazlovitskaya²

2012

Tumor Angiogenesis

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Benzyl and Naphthalene Methylphosphonic Acid Inhibitors of Autotaxin with Anti‐invasive and Anti‐metastatic Activity

et al. 2011

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Autotaxin (ATX, NPP2) is a member of the nucleotide pyrophosphate phosphodiesterase enzyme family. ATX catalyzes the hydrolytic cleavage of lysophosphatidylcholine (LPC) via a lysophospholipase D activity that leads to the generation of the growth factor-like lipid mediator lysophosphatidic acid (LPA). ATX is highly upregulated in metastatic and chemotherapy-resistant carcinomas and represents a potential target to mediate cancer invasion and metastasis. Here we report the synthesis and pharmacological characterization of inhibitors of ATX based on the 4-tetradecanoylaminobenzyl phosphonic acid scaffold that was previously found to lack sufficient stability in cellular systems. The new 4-substituted benzyl phosphonic acid and 6-substituted naphthalen-2-yl-methyl phosphonic acid analogs blocked ATX with Ki values in the low-micromolar-nanomolar range against FS-3, LPC, and nucleotide substrates through a mixed-mode mechanism of inhibition. None of the compounds tested inhibited the activity of related enzymes (NPP6 and NPP7). In addition, the compounds were evaluated as agonists or antagonists of seven LPA receptor subtypes. Analogs 22 and 30b, the two most potent ATX inhibitors, dose-dependently inhibited the invasion of MM1 hepatoma cells across murine mesothelial and human vascular endothelial monolayers in vitro. The average terminal half-life for compound 22 was 10h ± 5.4h and it caused a long-lasting reduction plasma LPA levels. Compounds 22 and 30b significantly reduced lung metastasis of B16-F10 syngeneic mouse melanoma in a post-inoculation treatment paradigm. The described 4-substituted benzyl phosphonic acids and 6-substituted naphthalen-2-yl-methyl phosphonic acids represent new lead compounds that effectively inhibit the ATX-LPA-LPA receptor axis both in vitro and in vivo.

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Therapeutic Potentials of Ecto‐Nucleoside Triphosphate Diphosphohydrolase, Ecto‐Nucleotide Pyrophosphatase/Phosphodiesterase, Ecto‐5′‐Nucleotidase, and Alkaline Phosphatase Inhibitors

al‐Rashida

Iqbal

2013

Medicinal Research Reviews

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The modulatory role of extracellular nucleotides and adenosine in relevance to purinergic cell signaling mechanisms has long been known and is an object of much research worldwide. These extracellular nucleotides are released by a variety of cell types either innately or as a response to patho-physiological stress or injury. A variety of surface-located ecto-nucleotidases (of four major types; nucleoside triphosphate diphosphohydrolases or NTPDases, nucleotide pyrophosphatase/phosphodiesterases or NPPs, alkaline phosphatases APs or ALPs, and ecto-5'-nucleotidase or e5NT) are responsible for meticulously controlling the availability of these important signaling molecules (at their respective receptors) in extracellular environment and are therefore crucial for maintaining the integrity of normal cell functioning. Overexpression of many of these ubiquitous ecto-enzymes has been implicated in a variety of disorders including cell adhesion, activation, proliferation, apoptosis, and degenerative neurological and immunological responses. Selective inhibition of these ecto-enzymes is an area that is currently being explored with great interest and hopes remain high that development of selective ecto-nucleotidase inhibitors will prove to have many beneficial therapeutic implications. The aim of this review is to emphasize and focus on recent developments made in the field of inhibitors of ecto-nucleotidases and to highlight their structure activity relationships wherever possible. Most recent and significant advances in field of NTPDase, NPP, AP, and e5NT inhibitors is being discussed in detail in anticipation of providing prolific leads and relevant background for research groups interested in synthesis of selective ecto-nucleotidase inhibitors.

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Characterization of non-lipid autotaxin inhibitors

Cited by 24 publications

References 64 publications

New Molecular Targets for Anti-Angiogenic Therapeutic Strategies

New Molecular Targets for Anti-Angiogenic Therapeutic Strategies

Benzyl and Naphthalene Methylphosphonic Acid Inhibitors of Autotaxin with Anti‐invasive and Anti‐metastatic Activity

Therapeutic Potentials of Ecto‐Nucleoside Triphosphate Diphosphohydrolase, Ecto‐Nucleotide Pyrophosphatase/Phosphodiesterase, Ecto‐5′‐Nucleotidase, and Alkaline Phosphatase Inhibitors

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