TY - JOUR
T1 - Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation
AU - Albers, Harald M.H.G.
AU - Dong, Anping
AU - Van Meeteren, Laurens A.
AU - Egan, David A.
AU - Sunkara, Manjula
AU - Van Tilburg, Erica W.
AU - Schuurman, Karianne
AU - Van Tellingen, Olaf
AU - Morris, Andrew J.
AU - Smyth, Susan S.
AU - Moolenaar, Wouter H.
AU - Ovaa, Huib
PY - 2010/4/20
Y1 - 2010/4/20
N2 - Autotaxin (ATX) is a secreted nucleotide pyrophosphatase/phosphodiesterase that functions as a lysophospholipase D to produce the lipid mediator lysophosphatidic acid (LPA), a mitogen, chemoattractant, and survival factor for many cell types. The ATX-LPA signaling axis has been implicated in angiogenesis, chronic inflammation, fibrotic diseases and tumor progression, making this system an attractive target for therapy. However, potent and selective nonlipid inhibitors of ATX are currently not available. By screening a chemical library, we have identified thiazolidinediones that selectively inhibit ATX-mediated LPA production both in vitro and in vivo. Inhibitor potency was approximately 100-fold increased (IC50 ∼ 30 nM) after the incorporation of a boronic acid moiety, designed to target the active-site threonine (T210) in ATX. Intravenous injection of this inhibitor into mice resulted in a surprisingly rapid decrease in plasma LPA levels, indicating that turnover of LPA in the circulation is much more dynamic than previously appreciated. Thus, boronic acid-based small molecules hold promise as candidate drugs to target ATX.
AB - Autotaxin (ATX) is a secreted nucleotide pyrophosphatase/phosphodiesterase that functions as a lysophospholipase D to produce the lipid mediator lysophosphatidic acid (LPA), a mitogen, chemoattractant, and survival factor for many cell types. The ATX-LPA signaling axis has been implicated in angiogenesis, chronic inflammation, fibrotic diseases and tumor progression, making this system an attractive target for therapy. However, potent and selective nonlipid inhibitors of ATX are currently not available. By screening a chemical library, we have identified thiazolidinediones that selectively inhibit ATX-mediated LPA production both in vitro and in vivo. Inhibitor potency was approximately 100-fold increased (IC50 ∼ 30 nM) after the incorporation of a boronic acid moiety, designed to target the active-site threonine (T210) in ATX. Intravenous injection of this inhibitor into mice resulted in a surprisingly rapid decrease in plasma LPA levels, indicating that turnover of LPA in the circulation is much more dynamic than previously appreciated. Thus, boronic acid-based small molecules hold promise as candidate drugs to target ATX.
KW - High-throughput screening
KW - Lysophosphatidic acid
KW - Lysophospholipase D
KW - Phosphodiesterase
KW - Small-molecule inhibitor
UR - https://www.scopus.com/pages/publications/77952173274
UR - https://www.scopus.com/pages/publications/77952173274#tab=citedBy
U2 - 10.1073/pnas.1001529107
DO - 10.1073/pnas.1001529107
M3 - Article
C2 - 20360563
AN - SCOPUS:77952173274
SN - 0027-8424
VL - 107
SP - 7257
EP - 7262
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 16
ER -