Carbamoylphosphonates inhibit autotaxin and metastasis formation in vivo. (October 2015)

• Record Type: Journal Article
• Authors: Reich, Reuven; Hoffman, Amnon; Suresh, R. Rama; Shai, Ofra; Frant, Julia; Maresca, Alfonso; Supuran, Claudiu T.; Breuer, Eli
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 30:Number 5(2015:Oct.)
• Page Start: 767
• Page End: 772
• Publication Date: 2015-10
• Subjects: Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• Languages: English
• ISSNs: 1475-6366

Abstract

<abstract> <title>Abstract</title> <p>Autotaxin is an extracellular, two zinc-centered enzyme that hydrolyzes lysophosphatidyl choline to lysophosphatidic acid, involved in various cancerous processes, e.g. migration, proliferation and tumor progression. We examined the autotaxin inhibitory properties of extended structure carbamoylphosphonates (CPOs) PhOC₆H₄SO₂NH(CH₂)<italic>_n</italic>NHCOPO₃H₂, with increasing lengths of methylene chains, (CH₂)<italic>_n, n</italic> = 4–8. Carbamoylphosphonates having <italic>n</italic> = 6, 7, 8 inhibited autotaxin <italic>in vitro</italic> with IC₅₀ ≈ 1.5 µM. Using an imaging probe we demonstrated that compound <italic>n</italic> = 6 inhibits recombinant autotaxin activity <italic>in vitro</italic> and <italic>in vivo, </italic> following oral CPO administration. Additionally, daily oral administration of compound <italic>n</italic> = 7 inhibited over 90% of lung metastases in a murine melanoma metastasis model. Both the carbamoylphosphonates and the enzymes reside and interact in the extracellular space expecting minimal toxic side effects, and presenting a novel approach for inhibiting tumor proliferation and metastasis dissemination.</p> </abstract>