Journal
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Volume 30, Issue 5, Pages 767-772Publisher
TAYLOR & FRANCIS LTD
DOI: 10.3109/14756366.2014.968146
Keywords
Autotaxin; carbamoylphosphonate; carbonic anhydrase; matrix metalloproteinase
Funding
- Grass Center for Drug Design and Synthesis of Novel Therapeutics
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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)(n)NHCOPO3H2, with increasing lengths of methylene chains, (CH2)(n), n = 4-8. Carbamoylphosphonates having n = 6, 7, 8 inhibited autotaxin in vitro with IC50 approximate to 1.5 mu M. 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.
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