Design of Anticancer Lysophosphatidic Acid Agonists and Antagonists

Abstract

Lysophosphatidic acid (LPA) and its receptors, LPA1-6, are integral parts of signaling pathways involved in cellular proliferation, migration and survival. These signaling pathways are of therapeutic interest for the treatment of multiple types of cancer and to reduce cancer metastasis and side effects. Validated therapeutic potential of key receptors, as well as recent structure-activity relationships yielding compounds with low nanomolar potencies are exciting recent advances in the field. Some compounds have proven efficacious in vivo against tumor proliferation and metastasis, bone cancer pain and the pulmonary fibrosis that can result as a side effect of pulmonary cancer radiation treatment. However, recent studies have identified that LPA contributes through multiple pathways to the development of chemotherapeutic resistance suggesting new applications for LPA antagonists in cancer treatment. This review summarizes the roles of LPA signaling in cancer pathophysiology and recent progress in the design and evaluation of LPA agonists and antagonists.

Lysophosphatidic Acid Signaling in Cancer Cells: What Makes LPA So Special?

“…LPA is particularly efficacious at activating Rho [29]. LPARs as potential therapeutic targets and the LPA "axis" in cancer have been reviewed on multiple occasions over the years [1,15,18,20,[30][31][32], including in the current Special Issue [33].…”

The autotaxin-lysophosphatidic acid–lysophosphatidic acid receptor cascade: proposal of a novel potential therapeutic target for treating glioblastoma multiforme

“…A detailed analysis of the pharmacological properties of synthetic inhibitors, including solubility, toxicity, pharmacokinetics, bioavailability, and permeability will be important in the effort to move these drugs into clinical use [ 127 ]. Clinical trials serve as the penultimate step on the path toward clinical use in the treatment of human cancers including GBM [ 128 ]. Several LPAR-specific analogues and small molecules have been synthesized.…”

The status of the lysophosphatidic acid receptor type 1 (LPA1R)

“…Although much research is ongoing in this eld, 64 the lack of potent and selective ligands is still an issue. Lipid-resembling molecules encounter solubility problems and show very high protein binding with only a small percentage within plasma available to interact with receptors.…”