Phosphatase-resistant analogues of lysophosphatidic acid: agonists promote healing, antagonists and autotaxin inhibitors treat cancer.
Isoform-selective agonists and antagonists of the lysophosphatidic acid (LPA) G protein-coupled receptors (GPCRs) have important potential applications in cell biology and therapy. LPA GPCRs regulate cancer cell proliferation, invasion, angiogenesis, and also biochemical resistance to chemotherapy- and radiotherapy-induced apoptosis. LPA and its analogues also are feedback inhibitors of the enzyme lysophospholipase D (lysoPLD, a.k.a., autotaxin, ATX), a central regulator of invasion and metastasis. For cancer therapy, the optimal therapeutic profile would be a metabolically-stabilized, pan-LPA receptor antagonist that also inhibited lysoPLD. For protection of gastrointestinal mucosa and lymphocytes, LPA agonists would be desirable to minimize or reverse radiation or chemical-induced injury. Analogues of lysophosphatidic acid (LPA) that are chemically modified to be less susceptible to phospholipases and phosphatases show activity as long-lived receptor-specific agonists and antagonists for LPA receptors, as well as inhibitors for the lysoPLD activity of ATX.
Prestwich
Glenn D
GD
Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, Utah 84108, USA. gprestwich@pharm.utah.edu
Gajewiak
Joanna
J
Zhang
Honglu
H
Xu
Xiaoyu
X
Yang
Guanghui
G
Serban
Monica
M
D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*
D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D010744:Phosphoric Monoester Hydrolases; D011755:Pyrophosphatases; C032881:lysophosphatidic acid