351336-10-2Relevant academic research and scientific papers
Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation
Albers, Harald M. H. G.,Dong, Anping,Van Meeteren, Laurens A.,Egan, David A.,Sunkara, Manjula,Van Tilburg, Erica W.,Schuurman, Karianne,Van Tellingen, Olaf,Morris, Andrew J.,Smyth, Susan S.,Moolenaar, Wouter H.,Ovaa, Huib
, p. 7257 - 7262 (2010)
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.
SP1-independent inhibition of FOXM1 by modified thiazolidinediones
Tabatabaei Dakhili, Seyed Amirhossein,Pérez, David J.,Gopal, Keshav,Haque, Moinul,Ussher, John R.,Kashfi, Khosrow,Velázquez-Martínez, Carlos A.
, (2020/10/21)
This research article describes an approach to modify the thiazolidinedione scaffold to produce test drugs capable of binding to, and inhibit, the in vitro transcriptional activity of the oncogenic protein FOXM1. This approach allowed us to obtain FOXM1 i
Discovery and optimization of boronic acid based inhibitors of Autotaxin
Albers, Harald M. H. G.,Van Meeteren, Laurens A.,Egan, David A.,Van Tilburg, Erica W.,Moolenaar, Wouter H.,Ovaa, Huib
experimental part, p. 4958 - 4967 (2010/09/10)
Autotaxin (ATX) is an extracellular enzyme that hydrolyzes lysophosphatidylcholine (LPC) to produce the lipid mediator lysophosphatidic acid (LPA). The ATX-LPA signaling axis has been implicated in diverse physiological and pathological processes, including vascular development, inflammation, fibrotic disease, and tumor progression. Therefore, targeting ATX with small molecule inhibitors is an attractive therapeutic strategy. We recently reported that 2,4-thiazolidinediones inhibit ATX activity in the micromolar range. Interestingly, inhibitory potency was dramatically increased by introduction of a boronic acid moiety, designed to target the active site threonine in ATX. Here we report on the discovery and further optimization of boronic acid based ATX inhibitors. The most potent of these compounds inhibits ATX-mediated LPC hydrolysis in the nanomolar range (IC50 = 6 nM). The finding that ATX can be targeted by boronic acids may aid the development of ATX inhibitors for therapeutic use.
