Chemical Evolution of Autotaxin Inhibitors

Albers, Harald M. H. G.; Ovaa, Huib

doi:10.1021/cr2003213

Cited by 67 publications

(73 citation statements)

References 70 publications

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“…Because LPA is rapidly turned over, plasma LPA levels fall by >95﹪ upon treatment with a potent ATX inhibitor [140] . There are numerous small non-lipid molecules that have been discovered and modified to inhibit ATX activity through screening large libraries of compounds [141][142] . Unlike classical lipid analogs, these inhibitors tend to have better oral bioavailability due to their decreased hydrophobicity and they are unlikely to be degraded rapidly by endogenous hydrolytic pathways [143] .…”

Section: Atx Inhibitorsmentioning

confidence: 99%

Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo

2016

J Biomed Res

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Extracellular lysophosphatidate (LPA) is a potent bioactive lipid that signals through six G-protein-coupled receptors. This signaling is required for embryogenesis, tissue repair and remodeling processes. LPA is produced from circulating lysophosphatidylcholine by autotaxin (ATX), and is degraded outside cells by a family of three enzymes called the lipid phosphate phosphatases (LPPs). In many pathological conditions, particularly in cancers, LPA concentrations are increased due to high ATX expression and low LPP activity. In cancers, LPA signaling drives tumor growth, angiogenesis, metastasis, resistance to chemotherapy and decreased efficacy of radiotherapy. Hence, targeting the ATX-LPA-LPP axis is an attractive strategy for introducing novel adjuvant therapeutic options. In this review, we will summarize current progress in targeting the ATX-LPA-LPP axis with inhibitors of autotaxin activity, LPA receptor antagonists, LPA monoclonal antibodies, and increasing low LPP expression. Some of these agents are already in clinical trials and have applications beyond cancer, including chronic inflammatory diseases.

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Section: Atx Inhibitorsmentioning

confidence: 99%

Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo

2016

J Biomed Res

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“…46,52,71,72 Moreover, various antagonists and agonists of LPA receptors and ATX inhibitors are being developed to explore their therapeutic potential in targeted treatments for different diseases. 52,73,74 Similar to LPA, S1P is also a pleiotropic bioactive lipid mediator that acts extracellularly via specific GPCRs on the cell surface and intracellularly via distinct target sites. 45,51 S1P is produced from sphingosine by sphingosine kinase (SK).…”

Section: 63mentioning

confidence: 99%

“…62,105,106 Therefore, the development of ATX inhibitors has engendered a great deal of interest from pharmaceutical companies. 74,98 Human TM cells express all 3 isoforms of ATX. 43 In human AH, ATX was identified as one of the abundant proteins based on quantitative proteomics.…”

Section: Lysophospholipids In Regulation Of Ah Outflow and Iopmentioning

confidence: 99%

“…82 Development and characterization of ATX-specific inhibitors is being actively explored for the treatment of different diseases. 74 Therefore, there is an opportunity to test the translational benefit of several of these small molecular inhibitors in lowering IOP and treatment of glaucoma. For proof of concept, in addition to testing the effects of ATX inhibitors on IOP, it is necessary to target the expression of ATX in the AH outflow pathway or TM tissue using ATX siRNA and determining their specific effects on AH outflow.…”

Section: Lysophospholipids In Regulation Of Ah Outflow and Iopmentioning

confidence: 99%

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Bioactive Lysophospholipids: Role in Regulation of Aqueous Humor Outflow and Intraocular Pressure in the Context of Pathobiology and Therapy of Glaucoma

Rao

2014

Journal of Ocular Pharmacology and Therapeutics

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Homeostasis of aqueous humor (AH) outflow and intraocular pressure (IOP) is essential for normal vision. Impaired AH outflow through the trabecular meshwork (TM) and a resultant elevation in IOP are common changes in primary open-angle glaucoma (POAG), which is the most prevalent form of glaucoma. Although elevated IOP has been recognized as a definitive risk factor for POAG and lowering elevated IOP remains a mainstay for glaucoma treatment, little is known about the molecular mechanisms, especially external cues and intracellular pathways, involved in the regulation of AH outflow in both normal and glaucomatous eyes. In addition, despite the recognition that increased resistance to AH outflow via the conventional pathway consisting of TM and Schlemm's canal is the main cause for elevated IOP, there are no clinically approved drugs that target the conventional pathway to lower IOP in glaucoma patients. The aim of this article is to briefly review published work on the importance of bioactive lysophospholipids (eg, lysophosphatidic acid and sphingosine-1-phosphate), their receptors, metabolism, signaling, and role in the regulation of AH outflow via the TM and IOP, and to discuss pharmacological targeting of key proteins in the lysophospholipid signaling pathways to lower IOP in glaucoma patients.

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“…The latter is involved in diverse malignant processes such as migration, proliferation and differentiation 5 . ATX is at the focus of considerable effort to achieve clinically useful inhibitors, however so far without success 6 . Our research focuses on the inhibiting properties of carbamoylphosphonates (CPO) towards ATX.…”

Section: Introductionmentioning

confidence: 99%

Carbamoylphosphonates inhibit autotaxin and metastasis formationin vivo

Reich

Hoffman

Suresh

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Autotaxin is an extracellular, two zinc-centered enzyme that hydrolyzes lysophosphatidyl choline to lysophosphatidic acid, involved in various cancerous processes, e.g. migration, proliferation and tumor progression. We examined the autotaxin inhibitory properties of extended structure carbamoylphosphonates (CPOs) PhOC 6 H 4 SO 2 NH(CH 2 ) n NHCOPO 3 H 2 , with increasing lengths of methylene chains, (CH 2 ) n , n ¼ 4-8. Carbamoylphosphonates having n ¼ 6, 7, 8 inhibited autotaxin in vitro with IC 50 & 1.5 mM. Using an imaging probe we demonstrated that compound n ¼ 6 inhibits recombinant autotaxin activity in vitro and in vivo, following oral CPO administration. Additionally, daily oral administration of compound n ¼ 7 inhibited over 90% of lung metastases in a murine melanoma metastasis model. Both the carbamoylphosphonates and the enzymes reside and interact in the extracellular space expecting minimal toxic side effects, and presenting a novel approach for inhibiting tumor proliferation and metastasis dissemination.

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Chemical Evolution of Autotaxin Inhibitors

Cited by 67 publications

References 70 publications

Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo

Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo

Bioactive Lysophospholipids: Role in Regulation of Aqueous Humor Outflow and Intraocular Pressure in the Context of Pathobiology and Therapy of Glaucoma

Carbamoylphosphonates inhibit autotaxin and metastasis formationin vivo

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