Inhibitors of Autotaxin for Drug Resistant Cancer Stem Cells and Fibrotic Diseases
Published:7/10/2019Description:
The Technology Solution:
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 stimulates the motility of tumor cells and has angiogenic properties. It is highly upregulated in metastatic and chemotherapy-resistant carcinomas and represents an attractive target to mediate cancer invasion and metastasis.
Several oncology drug discovery programs have identified small molecule ATX inhibitors. These generally fall into two distinct families, lipid-like ATX inhibitors that mimic the natural LPC, and non-lipid ones. Lipid-like ATX inhibitors have liabilities because they often have unsuitable partition coefficients, limiting their therapeutic utility. Most known non-lipid ATX inhibitors feature an acid-like moiety to interact with one of the Zn2+ ions at the catalytic site. None of these inhibitors has successfully made it through clinical trials so far, which has been attributed to potential issues of toxicity and off-target effects due to the acidic moiety.
Researchers at the University of Tennessee Health Sciences Center have identified novel non lipid-like small molecule leads without acidic moiety which exert their catalytic activity by binding in the hydrophobic pocket of ATX and not the catalytic site. These new class of ATX inhibitors display the same anti-metastatic and anti-invasive effects as the ones that block the catalytic site. The identified leads block ATX activity with Ki values in the low nanomolar range and reduce melanoma metastasis and chemotherapeutic resistance in breast cancer stem cells.
Benefits:
- Lead structures inhibit ATX with low nanomolar potency in chemotherapeutic resistant breast cancer stem cells.
- Three of the potent ATX inhibitors are dual inhibitors that are also antagonizing LPA1 in a low single digit micro-molar potency.
- Robust and reliable synthesis in a few steps with commercially available chemicals.
Publications:
- FEBS Journal 281 (2014) 1017–1028
- J. Med. Chem., 2017, 60 (4), pp 1309–1324
Patents:
- US 16/305,345 and EP 17807549.5 and CAN 3,026,252.