Design and Development of Autotaxin Inhibitors

Abstract

Autotaxin (ATX) is the only enzyme of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP2) family with lysophospholipase D (lysoPLD) activity, which is mainly responsible for the hydrolysis of extracellular lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). LPA can induce various responses, such as cell proliferation, migration, and cytokine production, through six G protein-coupled receptors (LPA1-6). This signaling pathway is associated with metabolic and inflammatory disorder, and inhibiting this pathway has a positive effect on the treatment of related diseases, while ATX, as an important role in the production of LPA, has been shown to be associated with the occurrence and metastasis of tumors, fibrosis and cardiovascular diseases. From mimics of ATX natural lipid substrates to the rational design of small molecule inhibitors, ATX inhibitors have made rapid progress in structural diversity and design over the past 20 years, and three drugs, GLPG1690, BBT-877, and BLD-0409, have entered clinical trials. In this paper, we will review the structure of ATX inhibitors from the perspective of the transformation of design ideas, discuss the advantages and disadvantages of each inhibitor type, and put forward prospects for the development of ATX inhibitors in the future.

Inhibition of the enzyme autotaxin reduces cortical excitability and ameliorates the outcome in stroke

“…Although the translational potential of our study is clear, our findings are limited by the number of CSF samples available from patients with stroke and the absence of longitudinal patient CSF measurements, which would, however, be difficult to achieve due to ethical considerations. Furthermore, whereas ATX inhibition was a successful intervention in our animal stroke model, metabolic stability of an ATX inhibitor and its penetration through the blood-brain barrier may present further challenges on the way to the clinic ( 42 ).…”

Hepatocyte-Secreted Autotaxin Exacerbates Nonalcoholic Fatty Liver Disease Through Autocrine Inhibition of the PPARα/FGF21 Axis

“… 36 However, several clinical trials on the inhibitors of autotaxin (such as GLPG1690) and lysophosphatidic acid receptor antagonist (such as BMS-986020) were terminated because of severe adverse effects of these chemical compounds ( https://clinicaltrials.gov ). 72 Therapeutic antibodies have several advantages over small-molecule drugs with respect to target specificity, safety, and stability. In this connection, our study provides proof-of-concept evidence that antibody-mediated neutralization of autotaxin activity is highly efficacious in ameliorating fatty liver and NASH in 2 different mouse models, suggesting that the neutralizing antibodies against autotaxin may represent a promising strategy for drug development.…”

Autotaxin facilitates selective LPA receptor signaling

“…BBT-877 (Bridge Biotherapeutics Inc., Pangyo, South Korea), IOA-289 (iOnctura SA, Geneva, Switzerland), and cudetaxestat (Blade Therapeutics Inc., South San Francisco, USA) are now in phase 1/2 trials and are also type IV (or perhaps, for some, type III) inhibitors, displaying the common characteristic of occupying the ATX tunnel. None of the numerous potent type I orthosteric ATX inhibitors occupy the tunnel (iOnctura, 2021; Jia et al, 2021; Mulholland et al, 2020; Salgado-Polo and Perrakis, 2019), and none have entered clinical trials, to the best of our knowledge. These data raise the intriguing questions of whether and how the specific drug binding mode determines the physiological outcome of ATX/LPA signaling, both in vitro and in vivo .…”