Carbonic anhydrase inhibitors as antitumor/antimetastatic agents: a patent review (2008–2018)

ABSTRACT

Introduction: Human carbonic anhydrases (CA, EC 4.2.1.1) IX and XII are tumor-associated proteins, being part of the molecular machinery that tumor cells build as adaptive responses to hypoxia and acidic conditions characteristic of the ‘glycolytic shift’ of many tumors. A wealth of research depicts CA IX and CA XII as biomarkers and therapeutic targets for various cancer types.

Areas covered: The review presents an overview of the role of CA IX and CA XII in hypoxic tumors physio-pathology as well as the principal molecular, structural, and catalytic features of both isozymes. The review then covers the patent literature of medically relevant inhibitors of the tumor-associated CAs produced during the period 2008–2018.

Expert opinion: A variety of approaches and design strategies were reported which afford CA IX/XII-specific inhibitors and avoid the compromising effects of isoforms-promiscuous compounds. Access to the crystal structures of human CAs isoforms have improved structure-based drug design campaigns related to zinc-binder chemotypes. Nevertheless, great potential still resides in non-classical CAIs that exhibit alternative binding mechanisms able to further distinguish the various active sites architecture. CA IX inhibitors hybrids/conjugates are increasingly emerging in the field as promising therapeutic tools to combine CA inhibition to the anticancer effects of other moieties or antitumor drugs.

KEYWORDS:

• Carbonic anhydrase
• hypoxia
• HIF
• small molecule inhibitor
• antibody
• conjugate
• sulfonamide
• anti-tumor

Article highlights

• Isoforms IX and XII of the human carbonic anhydrases are tumor-related proteins, since they are highly overexpressed in a large number of solid tumors, where they actively contribute to survival and metastatic spread of cancer cells.

• The combined targeting of CA IX and CA XII represents an important challenge in the development of new anticancer drugs.

• A clear prevalence of patents dealing with CA IX (and XII) emerged over the last decade, reporting a collection of new compounds and antibodies.

• Most patents refer to CA inhibitors of the sulfonamide/sulfamate/sulfamide types that often lack selectivity for hCA IX and/or hCA XII over ubiquitous off-target isoforms.

• The tail approach allowed to achieve a consistent breakthrough in the design of zinc-binder CA IX/XII inhibitors. A ureido-tailed derivative, SLC-0111, was the first in-class selective CA IX/XII inhibitor progressing to clinical trials. It successfully completed and passed Phase I and was then scheduled in 2016 for Phase II for the treatment of advanced, metastatic solid tumors.

• A wealth of patent claims CA IX inhibitor conjugates for the treatment and imaging of cancers.

• Interesting perspectives in the field of anticancer CAIs are related to the development of CAIs possessing chemotypes different from the sulfonamides and their bioisosteres, such as coumarins, thiocoumarins, and sulfocoumarins.

This box summarizes key points contained in the article.

Acknowledgments

The authors thank Dr Sara Bua for editing the figures.

Declaration of interest

CTS declares a conflict of interest as he is an author of many patents dealing with various classes of CA inhibitors (most of which cited in the review). Research from authors’ group was financed by several European Union Projects (EUROXY, METOXIA, DeZnIT, and Dynano in the period 2004–2014) and by Signal Life Sciences (in the period 2013–2015). The authors were not paid for writing this review. 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.

Additional information

Funding

Ente Cassa di Risparmio di Firenze, Italy, is gratefully acknowledged for a grant to A.N (ECR 2016.0774).