Journal
MOLECULES
Volume 27, Issue 17, Pages -Publisher
MDPI
DOI: 10.3390/molecules27175487
Keywords
autotaxin (ATX); lysophosphatidic acid (LPA); lysophosphatidic acid receptor subtype-1 (LPAR1); dual inhibitors; combination therapy; cancer; metastasis; idiopathic pulmonary fibrosis (IPF)
Funding
- Middle Tennessee State University
- MTSU Molecular Biosciences Ph.D. program
- William and Ella Owens Medical Research Foundation
- NCI [CA092670]
- Harriet Van Vleet Endowment in Basic Oncology research
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The ATX-LPA-LPAR1 signaling pathway has a universal role in various cellular responses and is associated with metabolic and inflammatory diseases. Selective inhibitors have been developed, but their clinical efficacy in cancer and rheumatoid arthritis remains to be evaluated. Dual-targeting therapies show promise, although limited research has been done on dual ATX-LPAR1 inhibitors.
The ATX-LPA-LPAR1 signaling pathway plays a universal role in stimulating diverse cellular responses, including cell proliferation, migration, survival, and invasion in almost every cell type. The ATX-LPAR1 axis is linked to several metabolic and inflammatory diseases including cancer, fibrosis, and rheumatoid arthritis. Numerous selective ATX or LPAR1 inhibitors have been developed and so far, their clinical efficacy has only been evaluated in idiopathic pulmonary fibrosis. None of the ATX and LPAR1 inhibitors have advanced to clinical trials for cancer and rheumatoid arthritis. Nonetheless, several research groups, including ours, have shown considerable benefit of simultaneous ATX and LPAR1 inhibition through combination therapy. Recent research suggests that dual-targeting therapies are superior to combination therapies that use two selective inhibitors. However, limited reports are available on ATX-LPAR1 dual inhibitors, potentially due to co-expression of multiple different LPARs with close structural similarities at the same target. In this review, we discuss rational design and future directions of dual ATX-LPAR1 inhibitors.
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