Identification of Darmstoff analogs as selective agonists and antagonists of lysophosphatidic acid receptors

Gududuru, Veeresa; Zeng, Kui; Tsukahara, Ryoko; Makarova, Natalia; Fujiwara, Yuko; Pigg, Kathryn R.; Baker, Daniel L.; Tigyi, Gábor; Miller, Duane D.

doi:10.1016/j.bmcl.2005.08.096

Cited by 36 publications

(26 citation statements)

References 30 publications

(34 reference statements)

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“…These predictions fell short of expectations based on the training set results. Overall, model [33][34][35][36][37][38]40,54,55 A failed to be predictive for this closely related SAR series. Model B was shown to be 75% accurate in predicting active compounds and 40% accurate on inactive compounds, with a total accuracy of 56%.…”

Section: Resultsmentioning

confidence: 56%

Optimization of a Pipemidic Acid Autotaxin Inhibitor

Hoeglund

Bostic

Howard³

et al. 2009

J. Med. Chem.

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Autotaxin (ATX, NPP2) has recently been shown to be the lysophospholipase D responsible for synthesis of the bioactive lipid lysophosphatidic acid (LPA). LPA has a well-established role in cancer, and the production of LPA is consistent with the cancer-promoting actions of ATX. Increased ATX and LPA receptor expression have been found in numerous cancer cell types. The current study has combined ligand-based computational approaches (binary quantitative structure-activity relationship), medicinal chemistry, and experimental enzymatic assays to optimize a previously identified small molecule ATX inhibitor, H2L 7905958 (1). Seventy prospective analogs were analyzed via computational screening, from which 30 promising compounds were synthesized and screened to assess efficacy, potency, and mechanism of inhibition. This approach has identified four analogs as potent as or more potent than the lead. The most potent analog displayed an IC(50) of 900 nM with respect to ATX-mediated FS-3 hydrolysis with a K(i) of 700 nM, making this compound approximately 3-fold more potent than the previously described lead.

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Section: Resultsmentioning

confidence: 56%

Optimization of a Pipemidic Acid Autotaxin Inhibitor

Hoeglund

Bostic

Howard³

et al. 2009

J. Med. Chem.

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“…LPA and S1P are natural ATX inhibitors providing an approach for the development of ATX inhibitors. These include synthetic analogues of the naturally-occurring ATX-inhibitor cyclic phosphatidic acid (carba analogues of cyclic phosphatidic acid or ccPA), 109, 110 L-histidine, 111 VPC8a202, 112, 113 Darmstoff analogues, 114 Thiophosphoric acid O-octadec-9-enyl ester 115 and small molecular inhibitors identified using high-throughput screening. 116 Additional ATX inhibiting compounds are under development by multiple groups world-wide, attesting to the importance of this enzyme as a therapeutic target in tumorigenesis.…”

Section: Atx-lpa Receptor Axis In Breast and Ovarian Cancermentioning

confidence: 99%

ATX-LPA receptor axis in inflammation and cancer

Liu

Murph²,

Panupinthu

et al. 2009

Cell Cycle

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Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) mediates a plethora of physiological and pathological activities via interactions with a series of high affinity G protein-coupled receptors (GPCR). Both LPA receptor family members and autotaxin (ATX/LysoPLD), the primary LPA-producing enzyme, are aberrantly expressed in many human breast cancers and several other cancer lineages. Using transgenic mice expressing either an LPA receptor or ATX, we recently demonstrated that the ATX-LPA receptor axis plays a causal role in breast tumorigenesis and cancer-related inflammation, further validating the ATX-LPA receptor axis as a rich therapeutic target in cancer.

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“…recently described non-lipid ATX inhibitors,21-23 LPA analogs and metal chelators24 were the only known ATX inhibitors. LPA analogs showing ATX inhibition include sphingosine 1-phosphate,25 phosphonates,26-28 thiophosphates,27 cyclic glycerothiophosphates,29 carba cyclic phosphatidic acids,30 alpha-substituted phosphonic acids,31 and FTY720-phosphate 32. Since all published phospholipid ATX inhibitors are analogs of LPA, which does not exhibit simple competitive inhibition but rather shows mixed mode inhibition,25 they may not interact solely with the active site.…”

Section: Introductionmentioning

confidence: 99%

Autotaxin structure–activity relationships revealed through lysophosphatidylcholine analogs

North

Osborne

Bridson

et al. 2009

Bioorganic & Medicinal Chemistry

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Autotaxin (ATX) catalyzes the hydrolysis of lysophosphatidylcholine (LPC) to form the bioactive lipid lysophosphatidic acid (LPA). LPA stimulates cell proliferation, cell survival, and cell migration and is involved in obesity, rheumatoid arthritis, neuropathic pain, atherosclerosis and various cancers, suggesting that ATX inhibitors have broad therapeutic potential. Product feedback inhibition of ATX by LPA has stimulated structure activity studies focused on LPA analogs. However, LPA displays mixed mode inhibition, indicating it can bind to both the enzyme and the enzyme-substrate complex. This suggests that LPA may not interact solely with the catalytic site. In this report we have prepared LPC analogs to help map out substrate structure activity relationships. The structural variances include length and unsaturation of the fatty tail, choline and polar linker presence, acyl versus ether linkage of the hydrocarbon chain, and methylene and nitrogen replacement of the choline oxygen. All LPC analogs were assayed in competition with the synthetic substrate, FS-3, to show the preference ATX has for each alteration. Choline presence and methylene replacement of the choline oxygen were detrimental to ATX recognition. These findings provide insights into the structure of the enzyme in the vicinity of the catalytic site as well as suggesting that ATX produces rate enhancement, at least in part, by substrate destabilization.

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Identification of Darmstoff analogs as selective agonists and antagonists of lysophosphatidic acid receptors

Cited by 36 publications

References 30 publications

Optimization of a Pipemidic Acid Autotaxin Inhibitor

Optimization of a Pipemidic Acid Autotaxin Inhibitor

ATX-LPA receptor axis in inflammation and cancer

Autotaxin structure–activity relationships revealed through lysophosphatidylcholine analogs

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