Anticancer carbonic anhydrase inhibitors: a patent and literature update 2018-2022

ABSTRACT

Introduction

Cancer affects an increasing number of patients each year with an unacceptable death toll worldwide. A new therapeutic approach to combat tumors consists in targeting human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms IX and XII, which are tumor-associated, overexpressed enzymes in hypoxic tumors, being involved in metabolism, pH regulation, ferroptosis, and overall tumor progression.

Areas covered

Small molecule hCA IX/XII and antibody drug conjugate inhibitors targeting the two enzymes and their applications in the management of cancer are discussed.

Expert opinion

The available 3D crystal structures of hCA IX, XII as well as the off target isoforms hCA I and II, afforded structure-based drug design opportunities, which led to the development of various isoform-selective small molecule inhibitors belonging to diverse classes (sulfonamides, sulfamates, benzoxaboroles, selenols, coumarins, sulfocoumarins, and isocoumarins). Many patents focused on small inhibitors containing sulfonamide/sulfamide/sulfamide derivatives as well as hybrids incorporating sulfonamides and different antitumor chemotypes, such as cytotoxic drugs, kinase/telomerase inhibitors, P-gp and thioredoxin inhibitors. The most investigated candidate belonging to the class is the sulfonamide SLC-0111, in Phase Ib/II clinical trials for the management of advanced, metastatic solid tumors.

KEYWORDS:

• Carbonic anhydrase
• isoforms hCA IX
• hCA XII
• anticancer agents
• hypoxic tumor
• inhibitor
• antibody-drug conjugate

Article highlights

• hCA IX and hCA XII are highly expressed in hypoxic cancers, promoting tumor growth by regulating intracellular pH, metabolism, and ferroptosis.

• A large number of small molecule inhibitors were developed by using available three-dimensional crystal structures of these enzymes.

• Recent patents on anticancer CA inhibitors (CAIs) mainly claim small molecules containing sulfonamide, sulfamide, and sulfamate derivatives.

• Monoclonal antibodies (MAbs) and Mab-drug conjugates were also claimed as CAIs targeting hypoxic tumors.

• Nanoparticles and quantum dots derivatized with sulfonamide CAIs showed interesting imaging and therapeutic potential for targeting these enzymes.

Acknowledgments

The Authors SG Nerella and P Singh are thankful to the NIMHANS Bangalore and NIPER Hyderabad for resources and support. Work from Supuran laboratory was financed by the Italian Ministry for Education and Science (MIUR), grant PRIN: rot. 2017XYBP2R and by Ente Cassa di Risparmio di Firenze (ECRF), grant CRF2020.1395.

Author contributions statement

SG Nerella and P Singh collected the scientific and patent literature and developed the first draft of the manuscript. M Arifuddin and CT Supuran studied all the publications, organized the material, and drafted the final form of the manuscript.

Declaration of interests

CT Supuran is one of the discoverers of SLC-0111, a compound in clinical development. CT Supuran is Editor-in-Chief of the Expert Opinion on Therapeutic Patents. He was not involved in the assessment, peer review, or decision-making process of this paper. The authors have no other relevant affiliations of 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 paper was not funded.