Development and therapeutic potential of autotaxin small molecule inhibitors: From bench to advanced clinical trials

Abstract

Several years after its isolation from melanoma cells, an increasing body of experimental evidence has established the involvement of Autotaxin (ATX) in the pathogenesis of several diseases. ATX, an extracellular enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) into the bioactive lipid lysophosphatidic acid (LPA), is overexpressed in a variety of human metastatic cancers and is strongly implicated in chronic inflammation and liver toxicity, fibrotic diseases, and thrombosis. Accordingly, the ATX-LPA signaling pathway is considered a tractable target for therapeutic intervention substantiated by the multitude of research campaigns that have been successful in identifying ATX inhibitors by both academia and industry. Furthermore, from a therapeutic standpoint, the entry and the so far promising results of the first ATX inhibitor in advanced clinical trials against idiopathic pulmonary fibrosis (IPF) lends support to the viability of this approach, bringing it to the forefront of drug discovery efforts. The present review article aims to provide a comprehensive overview of the most important series of ATX inhibitors developed so far. Special weight is lent to the design, structure activity relationship and mode of binding studies carried out, leading to the identification of advanced leads. The most significant in vitro and in vivo pharmacological results of these advanced leads are also summarized. Lastly, the development of the first ATX inhibitor entered in clinical trials accompanied by its phase 1 and 2a clinical trial data is disclosed. Med Res Rev. 2019;39:976-1013. wileyonlinelibrary.com/journal/med 976 |

Genetic deletion of Autotaxin from CD11b+ cells decreases the severity of experimental autoimmune encephalomyelitis

“…The attenuation of EAE severity by the genetic deletion of ATX from CD11b + cells, also considering the other likely sources of ATX expression in the inflamed CNS, suggest possible therapeutic benefits of targeting ATX in EAE/MS. Indeed, pharmacologic potent ATX inhibition was recently reported to attenuate the development of EAE [48], timely with the booming discovery of novel ATX inhibitors [49].…”

Genetic deletion of Autotaxin from CD11b+ cells decreases the severity of experimental autoimmune encephalomyelitis

“…The attenuation of EAE severity by the genetic deletion of ATX from CD11b + cells, also considering the other likely sources of ATX expression in the inflamed CNS, suggest possible therapeutic benefits of targeting ATX in EAE/MS. Indeed, pharmacologic potent ATX inhibition was recently reported to attenuate the development of EAE [53], timely with the booming discovery of novel ATX inhibitors [54].…”

Structure-Based Discovery of Novel Chemical Classes of Autotaxin Inhibitors

“…Furthermore, ATX appears to have an allosteric hydrophobic channel which can accommodate the product LPA. This channel forms a T-junction with the active site and the hydrophobic pocket [ 5 , 26 , 27 , 28 ] and may serve as an entrance for the LPC substrate, and an exit for LPA, thus offering the necessary hydrophobic milieu for LPA delivery to its receptors [ 29 ].…”

“…The crucial role of ATX in the onset and progress of a multitude of severe disorders has attracted the interest of both the academic and industrial community towards the development of potent ATX inhibitors as drug-targets. Accordingly, several series of ATX inhibitors have been developed in the last decade ( Figure 1 ) [ 27 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. Some of them were discovered by performing high-throughput screening methods while others by rational design, using the solved crystal structure of ATX co-crystallized with inhibitors [ 24 , 25 , 40 , 41 ].…”