Anticancer drugs: where are we now?

KEYWORDS:

• Anticancer drugs
• carbonic anhydrases
• G-quadruplexes
• proteasome inhibitors
• tubulin polymerisation inhibitor

Cancer remains one of the most common diseases nowadays [1–3], and although being characterized by a huge heterogeneity and multiple manifestations, the relevant progress achieved in the last decades in genomics, molecular biology, crystallography, drug design and computational techniques led to the development of a large number of effective therapeutic agents, small molecules, antibodies and cell-based therapies, which took advantage mainly of the metabolic and physiological differences between normal and tumor cells [4–8], although at a rather high cost [6]. However, many tumors remain difficult or impossible to be treated or they develop drug resistance to clinically used agents [4–7], and thus, the search for innovative, more effective and less toxic anticancer drugs than those currently available is still continuing. Two issues of Expert Opinion on Therapeutic Patents, one published in 2023 [9–13] and the second one in 2024 [14–17], present the state of the art and the relevant discoveries of last years in the field.

The first review article [9] in the first issue deals with tumor associated carbonic anhydrases (CAs) as drug targets for the management of hypoxic metastatic tumors. This field is in a very rapid progress [18–21], since these enzymes are involved in pH regulation, CO₂/bicarbonate sensing, metabolism [21,22] and ferroptosis [23], and their targeting with small molecules or antibodies leads to significant antitumor effects, alone or in combination with other drugs [9]. One of the most advanced small molecule inhibitors, which is presently in Phase Ib/II clinical trials, is the sulfonamide SLC-0111, for which several clinical trials are ongoing [24], but many other compounds have been developed and are in various stages of preclinical assessment [9,18–21].

Natural products represent a highly important source of innovative chemotypes possessing a variety of pharmacological activities [25] including antitumor ones [10]. Thus, the review from Carradori’s group [10] in the first collection of articles presents the updated information in the field of natural products possessing anticancer activity, particularly reviewing the flavonoids, chalcones, stilbenes, xanthines, various alkaloids, lignans, cannabinoids, terpenes, terpenoids, and their anticancer mechanisms of action. This exhaustive review may allow medicinal chemists for new ideas in the design of this type of pharmacological agents based on a variety of structures which are presented in the article [10].

The article from Randazzo’s group [11] presents in detail the guanine-rich DNA sequences which fold into noncanonical, four-stranded secondary structures, known as G-quadruplexes (G4s), which are targetable for obtaining anticancer drugs [26,27]. The role of G4s as human oncogene promoters is presented in detail for various targets such as KRAS, NRAS, c-MYC, c-KIT, HIF, VEGF, etc., together with the classes of ligands which bind to them, leading to antitumor effects [11].

The proteasome inhibitors, a class of anticancer agents successfully introduced in oncological therapies two decades ago, are dealt with in the review from Ronca’s group [12]. From the first-generation, clinically used agents such as bortezomib, to the second-generation inhibitors such as carfilzomib and ixazomib and to the many new developments in the area, with a vast number of structural variants available, the article represents an updated review of the field. Furthermore, the detailed mechanism of inhibition based on biochemical and X-ray crystallographic studies are also presented in detail [12].

Tubulin inhibitors such as the taxanes, vinca alkaloid derivatives (vincristine and vinblastine), combretastatin, and many others, have been in clinical use for decades and although rather toxic, have a firm position in the anticancer therapies [7,13]. The review by Peerzada et al. [13] in the first collection of anticancer articles of the journal presents an exhaustive update on this target, presenting the various binding sites of the classical and new inhibitors to tubulin, as well as many novel principles for developing less toxic such compounds. In fact, many tubulin inhibitors (auristatin, maytansine, tubulysine, etc.) possess significant antitumor activity but are too toxic to be used clinically, and recent developments for their derivatization using cargo moieties (for the precise targeting only at the tumor site, avoiding thus severe side effects) have been proposed and worked better than the original, toxic compounds [28].

In the second collection, Gioiello and colleagues [14] present an interesting review article on the farnesoid X receptor (FXR), which is a key transcription factor involved in bile acid signaling, and ultimately shown to have connections also to tumorigenesis. Although at the moment only obeticholic acid (Ocaliva) has been approved for primary biliary cholangitis therapy as FXR agonist [29], the field is in constant evolution, with a high number of interesting compounds in Phase II/III clinical trials for various pathologies, including cancer. The review presents in detail all the latest developments with many natural and synthetic compounds presented from the scientific and patent literature [14].

The second paper in the second collection, by Rotili’s group [15] examines bromodomain and extra-terminal (BET) domain proteins, which are transcription cofactors recognizing acetylated lysines of histone (and also non-histone) proteins and can thus modulate gene expression. These proteins have been recognized as anticancer drug targets. The review examines the various strategies for obtaining BET inhibitors and their applications as antitumor agents.

Protein kinases (PKs) play many relevant roles in cell signaling and regulatory processes in physiologic and pathologic conditions [7] and are among the most investigated enzymes for the development of drugs modulating their activity. Tyrosine PK inhibitors have been in clinical use as antitumor agents for more than 20 years, with a rather large number of clinically approved agents available, which however easily lead to drug resistance problems [7,16]. The review by Carta et al. [16] thus presents the state-of-the-art in the field, with an update on the many new structural classes, their various applications and approaches for avoiding the rapid drug resistance emergence.

The review by Gasparrini et al. [17] deals with nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide (NAD), a fundamental molecule for all living processes. In addition to its role as redox cofactor, NAD also functions as a substrate for NAD-consuming enzymes, regulating multiple cellular processes such as DNA repair and gene expression, being thus involved in tumor growth. The review presents an update in the field of NAMPT inhibitors belonging to a large variety of chemotypes, which might soon lead to antitumor agents with innovative mechanisms of actions.

In conclusion, the two article collections on antitumor agents published in the last years in the journal provide a very positive reply to the question from the title of this Editorial: we are at a crucial point for the development of next generation anticancer agents. The valuable articles from the two collections [9–17] presented a multitude of drug targets and approaches for obtaining drugs, which are already validated or in course of being validated, demonstrating thus that this disease might become less terrible in the future for the millions of patients affected worldwide.

Declaration of interest

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.

Reviewer disclosures

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

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Funding

This paper was not funded.