title: 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) PhOC(6)H(4)SO(2)NH(CH(2))nNHCOPO(3)H(2), with increasing lengths of methylene chains, (CH(2))(n), n = 4-8. Carbamoylphosphonates having n = 6, 7, 8 inhibited autotaxin in vitro with IC(50) ≈ 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.
authors: a Institute for Drug Research , Hebrew University of Jerusalem , Jerusalem , Israel and.
authors: Reuven
authors: R
authors: Reich
authors: Amnon
authors: A
authors: Hoffman
authors: R Rama
authors: RR
authors: Suresh
authors: Ofra
authors: O
authors: Shai
authors: Julia
authors: J
authors: Frant
authors: Alfonso
authors: A
authors: Maresca
authors: Claudiu T
authors: CT
authors: Supuran
authors: Eli
authors: E
authors: Breuer
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D063065:Organophosphonates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000099189:Lysophospholipase D
chemical_list: D000970:Antineoplastic Agents; D063065:Organophosphonates; D010727:Phosphoric Diester Hydrolases; D013449:Sulfonamides; D000099189:Lysophospholipase D
keywords: Autotaxin; carbamoylphosphonate; carbonic anhydrase; matrix metalloproteinase