Clark, Jennifer M.; Salgado-Polo, Fernando; Macdonald, Simon J. F.; Barrett, Tim N.; Perrakis, Anastassis; Jamieson, Craig published the artcile< Structure-Based Design of a Novel Class of Autotaxin Inhibitors Based on Endogenous Allosteric Modulators>, Electric Literature of 167479-01-8, the main research area is structure based design steroid autotaxin inhibitors endogenous allosteric modulator.
Autotaxin (ATX) facilitates the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA), a bioactive phospholipid, which facilitates a diverse range of cellular effects in multiple tissue types. Abnormal LPA expression can lead to the progression of diseases such as cancer and fibrosis. Previously, we identified a potent ATX steroid-derived hybrid (partially orthosteric and allosteric) inhibitor which did not form interactions with the catalytic site. Herein, we describe the design, synthesis, and biol. evaluation of a focused library of novel steroid-derived analogs targeting the bimetallic catalytic site, representing an entirely unique class of ATX inhibitors of type V designation, which demonstrate significant pathway-relevant biochem. and phenotypic biol. effects. The current compounds modulated LPA-mediated ATX allostery and achieved indirect blockage of LPA1 internalization, in line with the observed reduction in downstream signaling cascades and chemotaxis induction. These novel type V ATX inhibitors represent a promising tool to inactivate the ATX-LPA signaling axis.
Journal of Medicinal Chemistry published new progress about Allosteric modulators. 167479-01-8 belongs to class iodides-buliding-blocks, and the molecular formula is C8H16INO2, Electric Literature of 167479-01-8.
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