Alkoxymethylenephosphonate analogues of (Lyso)phosphatidic acid stimulate signaling networks coupled to the LPA2 receptor

Joanna Gajewiak, Ryoko Tsukahara, Tamotsu Tsukahara, Shuanxing Yu, Yiling Lu, Mandi Murph, Gordon B. Mills, Gabor Tigyi, Glenn D. Prestwich

    Research output: Contribution to journalArticle

    10 Scopus citations

    Abstract

    An efficient stereocontrolled synthesis afforded alkoxymethylene- phosphonate (MP) analogues of lysophosphatidic acid (LPA) and phosphatidic acid (PA). The pharmacological properties of MP-LPA and MP-PA analogues were characterized for LPA receptor subtype-specific agonist and antagonist activity using Ca2+-mobilization assays in RH7777 cells expressing the individual LPA1-LPA3 receptors and CHO cells expressing LPA4. In addition, activation of a PPARγ reporter gene construct expressed in CV-1 cells was assessed. These metabolically stabilized LPA analogues exhibited an unexpected pattern of partial agonist/antagonist activity for the LPA G-protein-coupled receptor family and the intracellular LPA receptor PPARγ. Analogues were compared with 18:1 LPA for activation of downstream signaling in HT-29colon cancer cells, which exclusively express LPA2, and both SKOV3 and OVCAR3 ovarian cancer cells, which express LPA1, LPA2, and LPA3. Unexpectedly, reverse phase protein arrays showed that four MP-LPA and MP-PA analogues selectively activated downstream signaling in HT-29 cells with greater potency than LPA. In particular, the oleoyl MP-LPA analogue strongly promoted phosphorylation and activation of AKT, MEK, and pS6 in HT-29cells in a concentration-dependent manner. In contrast, the four MP-LPA and MP-PA analogues were equipotent with LPA for pathway activation in the SKOV3 and OVCAR3 cells. Taken together, these results suggest that the MP analogues may selectively activate signaling via the LPA2 receptor subtype, while simultaneously suppressing signaling through the LPA1 and LPA3 subtypes.

    Original languageEnglish (US)
    Pages (from-to)1789-1798
    Number of pages10
    JournalChemMedChem
    Volume2
    Issue number12
    DOIs
    StatePublished - Dec 10 2007

    Keywords

    • Agonists
    • GPCRs
    • Lysophosphatidic acid
    • Methylenephosphonates
    • Receptors

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Medicine
    • Pharmacology
    • Drug Discovery
    • Pharmacology, Toxicology and Pharmaceutics(all)
    • Organic Chemistry

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  • Cite this

    Gajewiak, J., Tsukahara, R., Tsukahara, T., Yu, S., Lu, Y., Murph, M., Mills, G. B., Tigyi, G., & Prestwich, G. D. (2007). Alkoxymethylenephosphonate analogues of (Lyso)phosphatidic acid stimulate signaling networks coupled to the LPA2 receptor. ChemMedChem, 2(12), 1789-1798. https://doi.org/10.1002/cmdc.200700111