Alkoxymethylenephosphonate analogues of (Lyso)phosphatidic acid stimulate signaling networks coupled to the LPA(2) receptor

作者：Gajewiak Joanna; Tsukahara Ryoko; Tsukahara Tamotsu; Fujiwara Yuko; Yu Shuanxing; Lu Wing; Murph Mandi; Mills Gordon B; Tigyi Gabor; Prestwich Gleen D^*

来源：ChemMedChem, 2007, 2(12): 1789-1798.

DOI：10.1002/cmdc.200700111

An efficient s tereocon trolled synthesis afforded alkoxymethylenephosphonate (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 LPA(1)-LPA(3) receptors and CHO cells expressing LPA(4). In addition, activation of a PPAR gamma 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 PPAR gamma. Analogues were compared with 18:1 LPA for activation of downstream signaling in HT-29 colon cancer cells, which exclusively express LPA(2,) and both SKOV3 and OVCAR3 ovarian cancer cells, which express LPA(1), LPA(2), and LPA(3). 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-29 cells in a concentration-dependent manner. In contrast, the four MP-LPA and MPPA 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 LPA(2) receptor subtype, while simultaneously suppressing signaling through the LPA(1) and LPA(3) subtypes.

• 出版日期2007-12