Discovery and Optimization of Boronic Acid Based Inhibitors of Autotaxin

Albers, Harald M. H. G.; Meeteren, Laurens A. van; Egan, David A.; Tilburg, Erica W. van; Moolenaar, Wouter H.; Ovaa, Huib

doi:10.1021/jm1005012

Cited by 66 publications

(102 citation statements)

References 33 publications

(80 reference statements)

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“…The potencies of two published ATX inhibitors, (Z)-(4-((4-((3-(4-fluorobenzyl)-2,4-dioxothiazolidin-5-ylidene)methyl) phenoxy)methyl)phenyl)boronic acid (HA155) (Albers et al, 2010) and 3,5-dichlorobenzyl 4-(3-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)propyl)piperazine-1-carboxylate (PF-8380) (Gierse et al, 2010), and four previously unpublished ATX inhibitors (PAT-078, PAT-347, PAT-494, and PAT-352) ( Fig. 2A) were determined against distinct enzymatic activities of ATX, including the lysoPLD and PPase/PDE activities, by using diverse substrates, including LPC, FS-3, and BNPP (Fig.…”

Section: Resultsmentioning

confidence: 99%

Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding

et al. 2015

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Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is a bioactive phospholipid that regulates diverse biological processes, including cell proliferation, migration, and survival/apoptosis, through the activation of a family of G protein-coupled receptors. The ATX-LPA pathway has been implicated in many pathologic conditions, including cancer, fibrosis, inflammation, cholestatic pruritus, and pain. Therefore, ATX inhibitors represent an attractive strategy for the development of therapeutics to treat a variety of diseases. Mouse and rat ATX have been crystallized previously with LPA or small-molecule inhibitors bound. Here, we present the crystal structures of human ATX in complex with four previously unpublished, structurally distinct ATX inhibitors. We demonstrate that the mechanism of inhibition of each compound reflects its unique interactions with human ATX. Our studies may provide a basis for the rational design of novel ATX inhibitors.

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Section: Resultsmentioning

confidence: 99%

Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding

et al. 2015

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“…Further, additional analysis is needed to determine whether other pathway alterations may serve compensatory roles in the small set of patients with ENPP2 deletions. Together, these results indicate that the ATX/LPA signaling axis may be dysregulated in specifi c cancer subtypes, and that patients could potentially benefi t from targeted therapies blocking ATX/ LPA signaling Due to the pleiotropic connection of ATX in cancer pathology, considerable effort has been made to generate small molecule inhibitors that target its enzymatic activity ( 120,(164)(165)(166)(167)(168)(169)(170)(171)(172)(173). Using sensitive fl uorescence probes, such as TG-mTMP, Kawaguchi et al ( 174 ) identifi ed several novel ATX inhibitor scaffolds and solved the crystal structures of ATX-compound complexes at high resolution (1.75-1.95 Å).…”

Section: Role In Physiology and Cancer Pathophysiologymentioning

confidence: 99%

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

Federico

Jeong

Vellano

et al. 2016

Journal of Lipid Research

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a 125 kDa glycoprotein composed of 915 amino acids ( 1 ). Because it promoted chemotaxis on melanoma cells in an autocrine fashion, the protein was aptly named auto-taxin. Four years after the discovery of the fi rst variant, now commonly referred to as ATX ␣ , or melanoma ATX, a second isoform was cloned by the same team from the teratocarcinoma cell line, Ntera2D1. This polypeptide shared 94% identity with the melanoma protein and was immediately recognized as the alternatively spliced product of the same gene ( 2 ).The initial characterization of the fi rst isoform revealed that ATX biological activity was sensitive to pertussis toxin treatment. Furthermore, not only did the polypeptide share close homology with the murine pyrophosphatase/ type I phosphodiesterase (PDE) PC-1, including a threonine residue crucial for PDE enzymatic activity, but it was also able to hydrolyze PDE substrates in vitro ( 3 ). The confi rmation that ATX was an enzyme came when a new PDE, the PDE1/nucleotide pyrophosphatase (PD-1 ␣ /PDNP 2), was cloned from a cDNA library of human retina and found to be identical to the sequence of melanoma ATX ␣ with the exception of a missing stretch of 52 amino acids encoded by exon 12 in the central region of the open reading frame. The transcript of this variant, now frequently referred to as ATX ␤ , or teratoma ATX, produced a 863 amino acid polypeptide chain with a mass of 99,034 Da ( 4 ), and was independently isolated a few years later in mouse tissues ( 5 ). The third ATX isoform was detected for the fi rst time in rat brain, but was originally designated as PD-I ␣ , a brain-specifi c PDE I/nucleotide pyrophosphatase ( 6 ). Further research showed that PD-I ␣ was identical to ATX ␤ teratoma protein, except for the presence of an additional stretch of 25 amino acids encoded by an alternatively Abstract The ectonucleotide pyrophosphatase/phosphodiesterase type 2, more commonly known as autotaxin (ATX), is an ecto-lysophospholipase D encoded by the human ENNP2 gene. ATX is expressed in multiple tissues and participates in numerous key physiologic and pathologic processes, including neural development, obesity, infl ammation, and oncogenesis, through the generation of the bioactive lipid, lysophosphatidic acid. Overwhelming evidence indicates that altered ATX activity leads to oncogenesis and cancer progression through the modulation of multiple hallmarks of cancer pathobiology. Here, we review the structural and catalytic characteristics of the ectoenzyme, how its expression and maturation processes are regulated, and how the systemic integration of its pleomorphic effects on cells and tissues may contribute to cancer initiation, progression, and therapy. Additionally, the up-to-date spectrum of the most frequent ATX genomic alterations from The Cancer Genome Atlas project is reported for a subset of cancers. ( Fig. 1 ). In 1992, the fi rst alternatively spliced isoform was cloned from the melanoma cell line, A2058, and characterized as STRUCTURE AND ENZYMATIC ACTIVITY ATX belongs to the nuc...

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“…18,19 Thus, many initially identified ATX inhibitors are lipid-like substrate or product analogs. 9,[165][166][167][168][169][170][171] The characteristics of this type of compounds limit their utility as potential lead compounds for drug development. Non-lipid ATX inhibitors have also been identified but most of these compounds lack sufficient potency and characterization in tumor models.…”

Section: Resultsmentioning

confidence: 99%

“…9,170,185 There is increasing interest in developing inhibitors of ATX to control the tumor promoting and pro-inflammatory roles of LPA. 166,167,170,[172][173][174][175]186 Carba cyclicphosphatidic acid was the first ATX inhibitor scaffold explored to control carcinoma invasion and metastasis in vivo. 9 Carba cyclic-phosphatidic acid inhibited ATX without activating LPA [1][2][3][4] .…”

Section: Atx Inhibitors Reduce B16 Melanoma Metastasis In Vivomentioning

confidence: 99%

“…170 LPA-BP inhibited breast cancer metastasis and tumor growth in vivo. 170 Several new ATX inhibitor scaffolds have been reported recently, 166,167,[172][173][174][175]186 however, these compounds have not been evaluated at other members of the NPP family and were not explored for their ability to control invasion and/or metastasis. Our study for the first time provides proof of the principle that non-lipid ATX inhibitors are capable of controlling cancer metastasis in vivo and also validate the monolayer invasion assay as a valuable cell-based screening for antimetastatic compounds.…”

Section: Atx Inhibitors Reduce B16 Melanoma Metastasis In Vivomentioning

confidence: 99%

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The Design and Synthesis of Autotaxin Inhibitors and Analogs of Lysophosphatidic Acid

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Discovery and Optimization of Boronic Acid Based Inhibitors of Autotaxin

Cited by 66 publications

References 33 publications

Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding

Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

The Design and Synthesis of Autotaxin Inhibitors and Analogs of Lysophosphatidic Acid

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