Carbamoylphosphonates inhibit autotaxin and metastasis formation in vivo

Abstract

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)_nNHCOPO₃H₂, with increasing lengths of methylene chains, (CH₂)_n, n = 4–8. Carbamoylphosphonates having n = 6, 7, 8 inhibited autotaxin in vitro with IC₅₀ ≈ 1.5 µM. Using an imaging probe we demonstrated that compound n = 6 inhibits recombinant autotaxin activity in vitro and in vivo, following oral CPO administration. Additionally, daily oral administration of compound n = 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.

• Autotaxin
• carbamoylphosphonate
• carbonic anhydrase
• matrix metalloproteinase

Acknowledgements

We highly appreciate Yael Ben-Nun's assistance with imaging analysis.

Declaration of interest

The authors declare no competing financial interest. This work was supported in part by the Grass Center for Drug Design and Synthesis of Novel Therapeutics to E.B. and R.R. A.H., R.R., and E.B. are affiliated with the David R. Bloom Center of Pharmacy and the Brettler Center for Pharmacology, in the School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem.