TY - JOUR
T1 - Carbamoylphosphonates inhibit autotaxin and metastasis formation in vivo
AU - Reich, Reuven
AU - Hoffman, Amnon
AU - Suresh, R. Rama
AU - Shai, Ofra
AU - Frant, Julia
AU - Maresca, Alfonso
AU - Supuran, Claudiu T.
AU - Breuer, Eli
N1 - Publisher Copyright:
© 2015 Informa UK Ltd. All rights reserved.
PY - 2015/9/3
Y1 - 2015/9/3
N2 - 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.
AB - 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.
KW - Autotaxin
KW - carbamoylphosphonate
KW - carbonic anhydrase
KW - matrix metalloproteinase
UR - http://www.scopus.com/inward/record.url?scp=84940663159&partnerID=8YFLogxK
U2 - 10.3109/14756366.2014.968146
DO - 10.3109/14756366.2014.968146
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C2 - 25669348
AN - SCOPUS:84940663159
SN - 1475-6366
VL - 30
SP - 767
EP - 772
JO - Journal of Enzyme Inhibition and Medicinal Chemistry
JF - Journal of Enzyme Inhibition and Medicinal Chemistry
IS - 5
ER -
