Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation

Albers, Harald M. H. G.; Dong, Anping; Meeteren, Laurens A. van; Egan, David A.; Sunkara, Manjula; Tilburg, Erica W. van; Schuurman, Karianne; Tellingen, Olaf van; Morris, Andrew J.; Smyth, Susan S.; Moolenaar, Wouter H.; Ovaa, Huib

doi:10.1073/pnas.1001529107

Cited by 187 publications

(217 citation statements)

References 34 publications

(35 reference statements)

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“…3B). We then examined whether ATX affects reactivation of the Xi by chemically inhibiting it with HA-130 (20). Addition of HA-130 to conversion medium did not affect production of GFP + cells (+ATXi).…”

Section: Resultsmentioning

confidence: 99%

Autotaxin-mediated lipid signaling intersects with LIF and BMP signaling to promote the naive pluripotency transcription factor program

Kime

Sakaki-Yumoto

Goodrich

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Developmental signaling molecules are used for cell fate determination, and understanding how their combinatorial effects produce the variety of cell types in multicellular organisms is a key problem in biology. Here, we demonstrate that the combination of leukemia inhibitory factor (LIF), bone morphogenetic protein 4 (BMP4), lysophosphatidic acid (LPA), and ascorbic acid (AA) efficiently converts mouse primed pluripotent stem cells (PSCs) into naive PSCs. Signaling by the lipid LPA through its receptor LPAR1 and downstream effector Rho-associated protein kinase (ROCK) cooperated with LIF signaling to promote this conversion. BMP4, which also stimulates conversion to naive pluripotency, bypassed the need for exogenous LPA by increasing the activity of the extracellular LPA-producing enzyme autotaxin (ATX). We found that LIF and LPA-LPAR1 signaling affect the abundance of signal transducer and activator of transcription 3 (STAT3), which induces a previously unappreciated Kruppel-like factor (KLF)2-KLF4-PR domain 14 (PRDM14) transcription factor circuit key to establish naive pluripotency. AA also affects this transcription factor circuit by controlling PRDM14 expression. Thus, our study reveals that ATX-mediated autocrine lipid signaling promotes naive pluripotency by intersecting with LIF and BMP4 signaling.

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Section: Resultsmentioning

confidence: 99%

Autotaxin-mediated lipid signaling intersects with LIF and BMP signaling to promote the naive pluripotency transcription factor program

Kime

Sakaki-Yumoto

Goodrich

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…We anticipated target engagement and lower LPA levels when exposures exceeded the plasma IC 80 . Due to the extremely short half-life of LPA in vivo, 16 autotaxin inhibition is accompanied by a nearly real-time reduction in plasma LPA. After a single oral dose (10 mg/kg) in normal rats, plasma concentrations of drug and LPA were monitored over 24 h. As shown in Figure 7, early time points demonstrated high plasma concentrations of 9 and concomitant low concentrations of LPA.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

Novel Autotaxin Inhibitors for the Treatment of Osteoarthritis Pain: Lead Optimization via Structure-Based Drug Design

Jones

Pfeifer

Bleisch

et al. 2016

ACS Med. Chem. Lett.

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ABSTRACT:In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC 50 of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstrated favorable potency (IC 50 = 2 nM), PK properties, and a robust PK/PD relationship. KEYWORDS: Autotaxin, tool molecule, osteoarthritis, LPA O steoarthritis (OA) is a highly prevalent disease affecting many adults including more than one out of three individuals aged 65 or older in the United States.1 In addition to significant accompanying pain, OA frequently leads to pronounced disability resulting in the loss of work, hospitalization, and joint replacement procedures.2 Current first-line pharmacological treatment options for OA focus on reducing inflammation and the associated pain. Nonsteroidal antiinflammatory drugs (NSAIDS) and selective COX-2 inhibitors are among the most prescribed medications for OA pain but unfortunately are also frequently accompanied by gastrointestinal, renal, and CV side effects, limiting their use. 3 Recently, the role of lyosophosphatidic acid (LPA) in certain inflammatory conditions has been studied. 4 LPA exists as a number of molecular species that have variable saturated and unsaturated fatty acid chains.5 Signaling of LPA through six GPCRs (LPA Receptors 1−6) has been shown to lead to the upregulation of inflammatory cytokines and matrix metalloproteinases, which contribute to the pathogenesis of OA. 6LPA signaling has also been associated with many other pathologies, such as pulmonary fibrosis and cancer. In vivo, the enzyme autotaxin (ATX), with lyosophosopholipase D activity, is the primary source of extracellular LPA, which results from the cleavage of choline from lysophosphatidylcholine (LPC) (Figure 1). LPA is also produced through action of secreted phospholipases A2 (sPLA2) on phosphatidic acid (PA), although this is believed to be a minor route of extracellular LPA production in vivo. 8,9 Autotaxin is an extracellular, 125 kDa protein that was originally characterized in 1993 by Stracke et al. as a motility stimulating protein. 10 In 2002, Umezu-Goto and co-workers demonstrated that ATX was the same protein as a known lysophopholipase D enzyme, which catalyzed the conversion of LPC to LPA.11 Autotaxin is a multidomain protein with two Nterminal somatomedin B-like domains, a centrally located phosphodiesterase domain, and a catalytically inactive nuclease-like domain on the C-terminal region. It is expressed in four main isoforms (ATXα−δ) with largely unknown differential functionality in vivo.7 The catalytic domain of ATX comprises two zinc ions coordinated with histidine and aspartic acid residues with a threonine alcohol serving as the nucleophile. A large hydro...

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“…Our results with the rat hypoxic model of PAH demonstrate for the first time an increased LPA serum level, compared to that in a control normoxic group. LPA is continuously produced by ATX (lysophospholipase D) in the plasma 25 and is directly consumed by cells or degraded by lipid phosphate phosphohydrolase. 26 So plasma measurements would not always reflect increased levels of LPA.…”

Section: Discussionmentioning

confidence: 99%

Possible Role of Lysophosphatidic Acid in Rat Model of Hypoxic Pulmonary Vascular Remodeling

Shlyonsky¹,

Naeije²,

Mies³

2014

Pulm. circ.

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Pulmonary hypertension is characterized by cellular and structural changes in the vascular wall of pulmonary arteries. We hypothesized that lysophosphatidic acid (LPA), a bioactive lipid, is implicated in this vascular remodeling in a rat model of hypoxic pulmonary hypertension. Exposure of Wistar rats to 10% O 2 for 3 weeks induced an increase in the mean serum levels of LPA, to 40.9 (log-detransformed standard deviations: 23.4 -71.7) μM versus 21.6 (11.0-42.3) μM in a matched control animal group (P ¼ 0.037). We also observed perivascular LPA immunohistochemical staining in lungs of hypoxic rats colocalized with the secreted lysophospholipase D autotaxin (ATX). Moreover, ATX colocalized with mast cell tryptase, suggesting implication of these cells in perivascular LPA production. Hypoxic rat lungs expressed more ATX transcripts (2.4-fold) and more transcripts of proteins implicated in cell migration: β2 integrin (1.74-fold), intracellular adhesion molecule 1 (ICAM-1; 1.84-fold), and αM integrin (2.70-fold). Serum from the hypoxic group of animals had significantly higher chemoattractant properties toward rat primary lung fibroblasts, and this increase in cell migration could be prevented by the LPA receptor 1 and 3 antagonists. LPA also increased adhesive properties of human pulmonary artery endothelial cells as well as those of human peripheral blood mononuclear cells, via the activation of LPA receptor 1 or 3 followed by the stimulation of gene expression of ICAM-1, β-1, E-selectin, and vascular cell adhesion molecule integrins. In conclusion, chronic hypoxia increases circulating and tissue levels of LPA, which might induce fibroblast migration and recruitment of mononuclear cells in pulmonary vasculature, both of which contribute to pulmonary vascular remodeling.Keywords: anti-lysophosphatidic acid antibody, fibroblast, circulating progenitor cells, cell migration and adhesion. INTRODUCTIONThe chronic-hypoxia model of pulmonary hypertension (PH) is characterized by an important remodeling of the arteriolar wall. This PH model is very predictable and reproducible, and although implication of vasoconstriction and vasoproliferation of the different cell types constituting the vascular wall has been shown, all the factors involved in these mechanisms are not yet identified. [1][2][3][4] Patients with PH can present with thrombotic pulmonary vascular lesions suggesting abnormalities of blood coagulation factors and platelet function. Hypoxia per se may accelerate blood coagulation 5 and platelet adhesion and aggregation. 6 The activation of platelets can result in the release of multiple and diverse soluble mediators such as

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Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation

Cited by 187 publications

References 34 publications

Autotaxin-mediated lipid signaling intersects with LIF and BMP signaling to promote the naive pluripotency transcription factor program

Autotaxin-mediated lipid signaling intersects with LIF and BMP signaling to promote the naive pluripotency transcription factor program

Novel Autotaxin Inhibitors for the Treatment of Osteoarthritis Pain: Lead Optimization via Structure-Based Drug Design

Possible Role of Lysophosphatidic Acid in Rat Model of Hypoxic Pulmonary Vascular Remodeling

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