Targeting carbonic anhydrases for the management of hypoxic metastatic tumors

ABSTRACT

Introduction

Several isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) are connected with tumorigenesis. Hypoxic tumors overexpress CA IX and XII as a consequence of HIF activation cascade, being involved in pH regulation, metabolism, and metastases formation. Other isoforms (CA I, II, III, IV) were also reported to be present in some tumors.

Areas Covered

Some CA isoforms are biomarkers for disease progression or response to therapy. Inhibitors, antibodies, and other procedures for targeting these enzymes for the treatment of tumors/metastases are discussed. Sulfonamides and coumarins represent the most investigated classes of inhibitors, but carboxylates, selenium, and tellurium-containing inhibitors were also investigated. Hybrid drugs of CA inhibitors with other antitumor agents for multitargeted therapy were reported.

Expert opinion

Targeting CAs present in solid or hematological tumors with selective, targeted inhibitors is a validated approach, which has been consolidated in the last years. A host of new preclinical data and several clinical trials of antibodies and small-molecule inhibitors are ongoing, which connected with the large number of new chemotypes/procedures discovered to be effective, may lead to a breakthrough in this therapeutic area. The scientific/patent literature has been searched for on PubMed, ScienceDirect, Espacenet, and PatentGuru, from 2018 to 2023.

KEYWORDS:

• carbonic anhydrase
• anticancer drugs
• hypoxic tumor
• inhibitors
• sulfonamides
• coumarins
• antibodies
• hybrid drugs

Article highlights

• hCA IX and hCA XII are expressed in hypoxic tumor cells, promoting growth and metastasis formation of solid and hematological tumors

• Isoforms such as hCA I, II, III, and IV were found in many tumor types, being considered as biomarkers or as novel therapeutic targets

• Exosomes from patients with tumors are enriched in cancer-associated CAs, such as CA IX

• A large number of inhibitors targeting these CAs connected to tumors are available, and many new chemotypes were also reported in the last period

• Sulfonamides and coumarins are the prevalently investigated CA inhibitors, with many isoform-selective compounds available to date

• Novel chemotypes, incorporating selenium and tellurium were obtained, which may contribute to the antitumor effects of the CA inhibitors by additional mechanisms of action

• Hybrid drugs incorporating CA inhibitors and other chemotypes (estrogen receptor modulators; vascular endothelial growth factor receptor 2 antagonists; H₂S releasing agents; signal transducer and transcriptional activator 3 inhibitors, and mono- and triterpenes) were reported to possess enhanced antitumor/antimetastatic effects

• Several MAbs and one sulfonamide small-molecule inhibitor (SLC-0111) are under clinical evaluation in various phases of development.

Declaration of interests

Claudiu T Supuran declares conflict of interest being the discoverer of SLC-0111 in phase Ib/II clinical trials. The author has no other 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.