Carbonic anhydrase inhibitors: an update on experimental agents for the treatment and imaging of hypoxic tumors

ABSTRACT

Introduction

Hypoxic tumors, unlike normal tissues, overexpress proteins involved in oxygen sensing, metabolism, pH regulation, angiogenesis, immunological response, and other survival mechanisms, which are under investigation as antitumor drug targets.

Areas covered

Carbonic anhydrase (CA) isoforms CA IX and XII are among these validated antitumor/antimetastatic drug targets, with several of their inhibitors undergoing preclinical or clinical-stage investigations. Alone or in combination with other chemotherapeutic agents or radiotherapy, CA IX/XII inhibitors, such as SLC-0111, SLC-149, S4, 6A10, etc., were shown to inhibit the growth of the primary tumor, metastases, and invasiveness of many tumor types, being also amenable for the development of imaging agents.

Expert Opinion

SLC-0111 is the most investigated agent, being in Phase Ib/II clinical trials. In addition to its interference with extracellular acidifications, it has been shown to promote ferroptosis in cancer cells, another antitumor mechanism of this compound and the entire class. A large number sulfonamide and non-sulfonamide inhibitors have been developed using SLC-0111 as lead in the last three years, together with hybrid agents incorporating CA inhibitors and other anticancer chemotypes, including cytotoxins, telomerase, thioredoxin or P-glycoprotein inhibitors, adenosine A₂A receptor antagonists, pyrophosphatase/phosphodiesterase-3 inhibitors or antimetabolites. All of them showed significant antitumor activity.

KEYWORDS:

• Antitumor drug
• carbonic anhydrase
• inhibitors
• hypoxia
• SLC-0111
• sulfonamide
• theragnostic agent

Declaration of interests

CT Supuran is one of the discoverers of SLC-0111. The authors have 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.

Article highlight

• Tumor associated CA isoforms CA IX and XII, overexpressed in many hypoxic tumors, are effective catalysts for the conversion of CO₂ in protons and bicarbonate.

• CA IX/XII are validated theragnostic antitumor targets, with many of their small molecule inhibitors in preclinical or clinical stages of development.

• Compounds in various stages of evaluation include the sulfonamides SLC-0111 and SLC-149, the sulfamate S4, and the monoclonal inhibitory antibody 6A10

• SLC-0111 and its congeners were demonstrated to have multiple antitumor mechanisms, among which inhibition of the extracellular acidification and promotion of feroptosis by interference with the intracellular alkalinization, which in turn is connected with the redox homeostasis via the cysteine desulfurase NFS1/cyst(e)ine transporter xCT axis.

• The results of the Phase I clinical trials of SLC-0111 published in 2020, showed a positive outcome and the recommended dosage for the Phase Ib/II trials, which are ongoing, is of 1000 mg/day.

• Many new CA IX/XII inhibitors were reported in the last years using SLC-0111 as lead molecule, some of which showed significant antitumor activity, together with a large number of drug hybrids incorporating CA inhibitors and other anticancer chemotypes, such as cytotoxins, telomerase, thioredoxin or P-glycoprotein inhibitors, adenosine A2A receptor antagonists, pyrophosphatase/ phosphodiesterase-3 inhibitors and antimetabolites.

Reviewer disclosures

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

Additional information

Funding

This paper is not funded.