Benzyl and naphthalene methylphosphonic acid inhibitors of autotaxin with anti-invasive and anti-metastatic activity

Gupte, R. and Patil, R. and Liu, J. and Wang, Y. and Lee, S. C. and Tigyi, Gábor (2011) Benzyl and naphthalene methylphosphonic acid inhibitors of autotaxin with anti-invasive and anti-metastatic activity. CHEMMEDCHEM, 6 (5). pp. 922-935. ISSN 1860-7179

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Autotaxin (ATX, NPP2) is a member of the nucleotide pyrophosphate phosphodiesterase enzyme family. ATX catalyzes the hydrolytic cleavage of lysophosphatidylcholine (LPC) by lysophospholipase D 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 K(i) 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 30 b, 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 compound 22 is 10+/-5.4 h and it causes a long-lasting decrease in plasma LPA levels. Compounds 22 and 30 b 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 in vitro and in vivo.

Item Type: Article
Additional Information: Tigyi G and Miller DD are co-senior authors.
Uncontrolled Keywords: I/*antagonists & inhibitors/metabolism; Organophosphorus Compounds/chemical synthesis/*chemistry/therapeutic use; Organophosphonates/chemical synthesis/*chemistry/therapeutic use; Neoplasm Metastasis; Neoplasm Invasiveness; Naphthalenes/chemical synthesis/*chemistry/therapeutic use; Multienzyme Complexes/*antagonists & inhibitors/metabolism; MICE; Melanoma, Experimental/drug therapy; Liver Neoplasms/drug therapy; Humans; Enzyme Inhibitors/chemical synthesis/*chemistry/therapeutic use; Disease Models, Animal; Cell Movement/drug effects; Cell Line, Tumor; Antineoplastic Agents/chemical synthesis/*chemistry/therapeutic use; Animals
Subjects: Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia
R Medicine / orvostudomány > R1 Medicine (General) / orvostudomány általában
Depositing User: MTMT SWORD
Date Deposited: 05 Oct 2017 14:28
Last Modified: 05 Oct 2017 14:28

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