Small-molecule CD73 inhibitors for the immunotherapy of cancer: a patent and literature review (2017–present)

ABSTRACT

Introduction

Hydrolysis of AMP to adenosine and inorganic phosphate is catalyzed by 5´-ectonucleotidase, e5NT, alias CD73, a metalloenzyme incorporating two zinc ions at its active site. e5NT is involved in crucial physiological and pathological processes, such as immune ho meostasis, inflammation, and tumor progression. CD73 inhibitors belonging to the monoclonal antibodies (MAbs) and small molecules started to be considered as candidates for the immunotherapy of tumors.

Areas covered

We review the drug design landscape in the scientific and patent literature on CD73 inhibitors from 2017 to the present. Small-molecule inhibitors were mostly discussed, although the MAbs are also considered.

Expert opinion

Considerable advances have been reported in the design of nucleotide/nucleoside-based CD73 inhibitors, after the X-ray crystal structure of the enzyme in complex with the non-hydrolyzable ADP analog, adenosine (α,β)-methylene diphosphate (AMPCP), was reported. A large number of highly effective such inhibitors are now available, through modifications of the nucleobase, sugar and zinc-binding groups of the lead. Few classes of non-nucleotide inhibitors were also reported, including flavones, anthraquinone ssulfonates, and primary sulfonamides. A highly potent ssmall-molecule CD73 inhibitor, AB680, is presently in the early phase of clinical trials as immunotherapeutic agents against various types of cancer.

KEYWORDS:

• 5´-ectonucleotidase
• cd73
• amp
• phosphonate
• adenosine
• baicaline
• nucleotide
• ab680

Article highlights

• Ectonucleotidase, e5NT, also known as CD73, catalyzes AMP hydrolysis to adenosine and inorganic phosphate.

• CD73 is a homodimeric zinc-containing enzyme in which two zinc ions per monomer are involved in the binding of AMP, its hhydrolysis, and the binding of most inhibitors.

• CD73 has two very different conformations, the open, butterfly-like form, and the closed form which is the catalytically effective one and to which the phosphonate inhibitors bind.

• The X-ray crystal structure of CD73 complexed with a non-hydrolyzable ADP analog, adenosine (α,β)-methylene diphosphate (AMPCP), was the starting point for the design of effective CD73 inhibitors.

• In the nucleotide-based CD73 inhibitors, modifications of the nucleobase, sugar and zinc-binding groups of the lead compound AMPCP have been performed, which led to highly effective, subnanomolar inhibitors.

• Non-nucleotide CD73 inhibitors were also reported, with anthraquinone sulfonates, sulfonamide, and some hydroxamates among the most interesting chemotypes.

• Few effective zinc-binding groups in the design of CD73 inhibitors are available except the phosphonate one.

• In tumors, CD73 regulates the production of immunosuppressive adenosine through the hydrolysis of AMP, and inhibiting the enzyme was shown to be beneficial as an antitumor mechanism.

• One small-molecule CD73 inhibitor, AB680, and several monoclonal antibodies, are presently in early stage clinical trials for the immunotherapy of different types of tumors.

• CD73 is overexpressed in the tumor microenvironment as a consequence of hypoxia-inducible factor HIF-1 activation, together with many other proteins, and the combination of CD73 inhibitors with antitumor agents targeting such proteins may be synergistic.

This box summarizes key points contained in the article.

Declaration of interest

CT Supuran is Editor-in-Chief of Expert Opinion on Therapeutic Patents and he was not involved in the assessment, peer review or decision-making process of this paper. 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 of this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.