Benzyl and naphthalene methylphosphonic acid inhibitors of autotaxin with anti-invasive and anti-metastatic activity
Autotaxin (ATX, NPP2) is a member of the nucleotide pyrophosphate phosphodiesterase enzyme family. ATX catalyzes the hydrolytic cleavage of lysophosphatidylcholine (LPC) by lysophospholipaseD activity, which leads to 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. Herein we report the synthesis and pharmacological characterization of ATX inhibitors based on the 4-tetradecanoylaminobenzylphosphonic acid scaffold, which was previously found to lack sufficient stability in cellular systems. The new 4-substituted benzylphosphonic acid and 6-substituted naphthalen-2-ylmethylphosphonic acid analogues block ATX activity with Ki values in the low micromolar to nanomolar range against FS3, LPC, and nucleotide substrates 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. Analogues 22 and 30b, the two most potent ATX inhibitors, inhibit the invasion of MM1 hepatoma cells across murine mesothelial and human vascular endothelial monolayers invitro in a dose-dependent manner. The average terminal half-life for compound 22 is 10±5.4h and it causes a long-lasting decrease in plasma LPA levels. Compounds 22 and 30b significantly decrease lung metastasis of B16-F10 syngeneic mouse melanoma in a post-inoculation treatment paradigm. The 4-substituted benzylphosphonic acids and 6-substituted naphthalen-2-ylmethylphosphonic acids described herein represent new lead compounds that effectively inhibit the ATX-LPA-LPAR axis both invitro and invivo. Inhibiting the ATX-LPA-LPAR axis: New 4-substituted benzylphosphonic acid and 6-substituted naphthalen-2-ylmethylphosphonic acid analogues were synthesized, and the most potent ATX inhibitors, 22 and 30b, show outstanding invivo profiles by diminishing lung metastases of B16-F10 syngeneic mouse melanoma in a post-inoculation treatment model. These two lead compounds effectively inhibit the ATX-LPA-LPAR axis both invitro and invivo. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Gupte, R., Patil, R., Liu, J., Wang, Y., Lee, S., Fujiwara, Y., Fells, J., & Bolen, A. (2011). Benzyl and naphthalene methylphosphonic acid inhibitors of autotaxin with anti-invasive and anti-metastatic activity. ChemMedChem, 6 (5), 922-935. https://doi.org/10.1002/cmdc.201000425