Small Molecule Inhibitors of Autotaxin for Cancer Therapeutics

Technical Field:

Cancer invasion and metastasis, lymphocyte recirculation, macular angiogenesis, allodynia and neuropathic pain, inflammation, cholestasis-associated pruritus.

The Technology:

Autotaxin (ATX, NPP2) is a member of the nucleotide pyrophosphate phosphodiesterase enzyme family.  ATX catalyzes the hydrolytic cleavage of lysophosphatidylcholine (LPC) that leads to the generation of the growth factor-like lipid mediator lysophosphatidic acid (LPA).  ATX is highly upregulated in metastatic and chemotherapy-resistant carcinomas and represents a potential target to mediate cancer invasion and metastasis.  ATX also regulates the re-entry of lymphocytes through the high endothelial venule cells in lymph nodes thus regulates lymphocyte trafficking and inflammation.  LPA generated by ATX has been shown to mediate angiogenesis responsible for the “wet”-type macular regeneration.

Researchers at the University of Tennessee Health Sciences Center have identified novel small molecules that block ATX activity with Ki values in the low micromolar to nanomolar range through a mixed-mode inhibition mechanism. None of the compounds tested inhibit the activity of related enzymes (NPP6 and NPP7). In addition, the compounds were evaluated as agonists or antagonists of seven LPA receptor (LPAR) subtypes.

• The two most potent ATX inhibitors inhibit the invasion of MM1 hepatoma cells across murine mesothelial and human vascular endothelial monolayers in vitro in a dose-dependent manner.
• The average terminal half-life for one of the lead compounds is 10 + 5.4 h and it causes a long-lasting decrease in plasma LPA levels.
• In vivo , the lead compounds significantly decrease lung metastasis of B16-F10 syngeneic mouse melanoma in a post-inoculation treatment paradigm. The lead compound also causes a 40% inhibition of the progression of bone metastasis in BALB/c nude mice.

Patents: US Patent 8,673,882 (granted) and PCT/US2012/021818 (applied)

Publications: Benzyl and Naphthalene Methylphosphonic Acid Inhibitors of Autotaxin with Anti-invasive and Anti-metastatic Activity; ChemMedChem 2011,6,922.

The Inventors

Dr. Duane Miller is the Harriett S. Van Vleet Professor, the Associate Dean for Research and Graduate Programs, and the Chair of the Department of Pharmaceutical Sciences in the College of Pharmacy at the University of Tennessee Health Sciences Center. In addition to his extensive record of academic research, his work has also been used as the foundation for two startup companies, and is a fundamental platform technology for a third.

Dr. Gabor Tigyi is the Chairman and Professor of Physiology, Harriet S. Van Vleet Chair in Oncology Research. Dr. Tigyi's group has made pioneering contributions to the current understanding of the pharmacology of phospholipid growth factors.  In collaboration with Dr. Miller they have developed several drug candidates targeting lysophospholipid signaling system.