An updated patent review of autotaxin inhibitors (2017–present)

ABSTRACT

Introduction

The ATX-LPA axis is an attractive target for therapeutic intervention in a variety of diseases, such as tumor metastasis, fibrosis, pruritus, multiple sclerosis, inflammation, autoimmune conditions, metabolic syndrome, and so on. Accordingly, considerable efforts have been devoted to the development of new chemical entities capable of modulating the ATX‐LPA axis.

Areas covered

This review aims to provide an overview of novel ATX inhibitors reported in patents from September 2016 to August 2020, discussing their structural characteristics and inhibitory potency in vitro and in vivo.

Expert opinion

In the past four years, the classification of ATX inhibitors based on binding modes has brought great benefits to the discovery of more efficacious inhibitors. In addition to GLPG1690 currently in phase III clinical studies for IPF, BBT-877, and BLD-0409 as potent ATX inhibitors have been enrolled in phase I clinical evaluation; meanwhile, many effective molecules were also reported successively. However, most emerging ATX inhibitors in the last four years are closely analogs of previous entities, such as GLPG1690 and PF-8380, which translate into the urgently identification of ATX inhibitors with diverse structural features and promising properties in the near future.

KEYWORDS:

• ATX inhibitor
• binding modes
• ATX-LPA axis
• fibrosis
• cancer

Article highlights

• The ATX-LPA axis is implicated in a variety of diseases.

• Depending on binding modes to the ATX tripartite site, small molecular inhibitors could be classified into four distinct types (I, II, III, and IV;).

• The structural characteristics and inhibitory efficacy of various potent ATX inhibitors reported in the past four years were discussed.

• Three ATX inhibitors (GLPG1690, BBT-877, and BLD-0409) have entered the clinical trials.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (No. 81872751), Key R&D Plan of Liaoning Province in 2020 (No. 2020020215-JH2/103), Development Project of the Ministry of Education Innovation Team (No. IRT1073).