Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 9, Issue 6, 2009

The use of compounds to affect the activity of proteins (both enzymes and receptors) is still under extensive consideration in the development of novel anti-tumour agents. In this issue, we consider a number of targets which have been (and continue to be) under investigation and which have shown therapeutic/clinical potential in the treatment of cancers. However, due to the nature of the area, it is difficult to undertake an extensive coverage of the use of small molecules against proteins within a journal issue, as such, the authors have attempted to provide the reader with a background into the general approach in the treatment of cancers through the use of protein modulators. The first paper by Aidoo-Gyamfi et al. covers one of the novel areas which have been shown to have clinical potential, namely the use of inhibitors of estrone sulfatase in the treatment of hormone-dependent breast cancer. The paper gives an overview of the area as well as discussing some compounds (for example, STX-213) which possess the potential to enter the clinic. The paper by Owen discusses another enzyme target within the steroidal cascade, namely, 17α-hydroxylase/17, 20-lyase, which has mainly been targeted in the treatment of androgen-dependent prostate cancer. A number of compounds have been targeted at this enzyme which has shown real potential, for example, abiraterone acetate has shown real promise in clinical trials, in particular, against refractory prostate cancer. This enzyme also has potential use in the treatment of estrogen-dependent breast cancer since it is a pivotal enzyme in the biosynthesis of the sex steroids. Indeed, 17α- hydroxylase/17, 20-lyase results in the biosynthesis of androgens which can therefore lead, via the action of the enzyme aromatase, to the biosynthesis of estrogens, the topic of the third paper by Banting and Ahmed. This paper therefore covers an enzyme which has shown real clinical significance through the emergence of drugs such as anastrozole and letrozole in the treatment of estrogen-dependent breast cancer. In his paper, Poirier discusses the inhibition of the enzyme 17β-hydroxysteroid dehydrogenase as this family of enzymes is involved in the transformation of weaker steroids (for example androstenedione or estrone) into the more potent sex steroids (for example testosterone and estradiol respectively) and vice versa. This enzyme has only recently become of importance since it was previously assumed to be a weak target due to non-specificity of the compounds since there are some 15 types of this enzyme which have been reported to exist. However, as discussed, a number of compounds have been shown to possess specificity and this enzyme has become a major target in the treatment of both hormone-dependent breast and prostate cancers. As such, these four papers represent the majority of the efforts directed towards the disruption of the steroidal cascade and therefore the treatment of hormone-dependent cancers. In the paper by Marson, the targeting of histone deacetylase is discussed with an overview of the different types of compound used to target this enzyme; the paper also discusses the potential use of inhibitors of this enzyme against refractory cancer. The paper by Winum et al. gives an extensive overview of the use of inhibitors against carbonic anhydrase, in particular, against isozyme IX of carbonic anhydrase. This isozyme has been implicated in the control of cell proliferation and cellular malignant transformation, indeed; its expression has been shown to be restricted in normal tissues but has been closely associated with different types of tumours, especially hypoxic solid tumours. Finally, Loew et al. discuss the targeting of epidermal growth factor receptor since it has been shown to be dysregulated in various tumour types including breast cancer and glioblastoma multiforme (GBM). In particular, treatments against GBM are discussed; a disease which is associated with a median survival of only 40 to 60 weeks from diagnosis, as such, this paper gives an insight into the achievements and challenges associated in the treatment of GBM. I believe, therefore, that this special issue will successfully introduce the reader to the challenges and achievements associated with a small number of targets which are under consideration in the treatment of various cancers.

A high proportion (∼40%) of breast cancers are hormone-dependent and it is the female hormone estradiol (E2) that is believed to play a key role in the initiation, promotion and progression of this disease. In the fight against this disease, compounds which are potent inhibitors of the cytochrome P-450 enzyme aromatase (AR) (which catalyses the conversion of the C19 androgens to the C18 estrogens) have been the major target. However, the administration of AR inhibitors alone does not prevent the localised biosynthesis of estrone (E1) (and therefore the subsequent synthesis of E2) within breast tumour cells via alternative non-AR routes. This has therefore been the major impetus for the development of steroid sulfatase (E1STS) inhibitors. The E1STS enzyme regulates the formation of E1 from estrone sulfate (E1S), a steroid conjugate present in high concentrations in tissue and blood in women with breast cancer. The STS enzyme has also been shown to catalyse the formation of dehydroepiandrosterone (DHEA) from DHEA-sulfate (DHEAS). This is important since DHEA can be converted to 5-androstene-3β,17β-diol, which has been shown to possess weak estrogenic properties, however, due to the high concentration of this steroid, it is able to stimulate the growth of breast cancer cells in vitro and in vivo. Considerable progress has been made in recent years in the development of a number of potent E1STS inhibitors, as such both steroidal and non-steroidal compounds have been considered and a number of highly potent inhibitors have been produced and evaluated against what is now considered a crucial enzyme in the fight against hormone-dependent breast cancer. The review therefore summarises the work that has been undertaken todate.

Prostate cancer is an age-related disease and a major cause of death in Western countries. A large proportion of prostate cancers have been found to be dependent on androgens for growth and various therapeutic approaches have aimed at either decreasing androgen levels or blocking their action. One method of decreasing androgen levels is through inhibition of enzymes involved in the biosynthetic pathway, for example, the P450 enzyme complex 17α-hydroxylase/C17,20-lyase (P45017α), which catalyses the conversion of pregnenolone and progesterone into the androgen precursors dehydroepiandrosterone and androstenedione respectively. A number of researchers have targeted this enzyme and have produced potent steroidal and non-steroidal inhibitors. This review looks at the various inhibitors that have been developed, focussing mainly on more recent inhibitors reported over the last ten years. Some mention is also given to structural requirements suggested to be important for potent activity.

The genetic control, mechanism of action and inhibition of aromatase for potential therapeutic benefits in the arena of hormone dependent illness continues to be of considerable interest. The work presented here concentrates on recent advances in the mechanistic aspects of the aromatase enzyme and the nature of the chemical entities that lead to its inhibition.

The 17β-hydroxysteroid dehydrogenases (17β-HSDs) are involved in the regulation of estrogens and androgens by catalyzing the reduction of 17-ketosteroids or the oxidation of 17β-hydroxysteroids. The enzyme activities associated with the different 17β-HSD isoforms are widespread in human tissues, not only in classic steroidogenic tissues but also in a large series of peripheral intracrine tissues. Being involved at the end of steroidogenesis, the numerous members of 17β-HSD family constitute interesting therapeutic targets for controlling the concentration of estrogens and androgens. Thus, inhibitors of reductive 17β-HSD isoforms are attractive to block the formation of hydroxysteroids that stimulate estrogeno-sensitive pathologies (breast, ovarian, and endometrium cancers) and androgenosensitive pathologies (prostate cancer, benign prostatic hyperplasia, acne, and hirsutism). The inhibitors could be used to block the degradation of estradiol, an attractive strategy for treating osteoporosis and Alzheimer's disease. In addition to their classical use as anti-cancer agents and therapeutic agents, inhibitors of 17β-HSDs are also useful tools to elucidate the role of these enzymes in particular biological systems. The present review article gives a description of novel inhibitors of 17β-HSDs that were published in 2003-2006.

Histone deacetylases (HDACs) remove acetyl groups from the tails of lysine residues of histone protein in nuclear chromatin and also from acetylated sites in non-histone proteins. HDACs and histone acetyltransferases (HATs) are major influences on the level of cellular protein acetylation, and an imbalance in acetylation levels, particularly under-acetylated (hypoacetylated) histone protein has been associated with precancerous or malignant states. Consequently, small molecule inhibitors of HDACs have been synthesised and some now form a newly emerging class of anti-cancer agents that can regulate transcription and inhibit proliferation of cancer cells by inducing cell cycle arrest, differentiation and/or apoptosis, among other major biological phenomena. The different mechanism(s) of action of HDAC inhibitors compared to conventional anti-neoplastic agents provides a possibility that HDAC inhibitors may be effective for refractory cancers. Accordingly, a number of programs for the development of HDAC inhibitors as anti-cancer drugs have been initiated. This review highlights recent developments in the design, synthesis and biological properties of HDAC inhibitors in the context of potential cancer therapy.

Of the thirteen active carbonic anhydrase (CA) isozymes, the transmembrane isoform CA IX has been shown to be linked with carcinogenesis. CA IX presents an ectopic expression in a multitude of carcinomas derived from cervix, uteri, kidney, lung, oesophagus, breast, colon, etc., contrasting with its restricted expression in normal tissues, namely in the epithelia of the gastrointestinal tract. It has been demonstrated that this membrane-bound CA is strongly overexpressed in hypoxic tumors, participating in tumor cell environment acidosis and contributing to malignant progression and poor treatment outcome. Targeting CA IX could thus be an important means of controlling cancer disease. Modulation of extracellular tumor pH via inhibition of CA IX activity represents a promising approach to novel anticancer therapies. Much attention has recently been paid to the CA IX inhibitors drug design, and efforts have been made to obtain isozyme IX inhibitors, with putative applications as antitumor drugs/diagnostic agents. This review will focus on the different CA IX inhibitors described in the literature which could represent excellent potential as candidate therapeutic agents in cancer chemotherapy.

The epidermal growth factor receptor (EGFR) is dysregulated in various tumour types such as glioblastoma multiforme (GBM), breast cancer, ovarian carcinoma, non-small cell lung cancer and other cancers. As the intracellular tyrosine kinase of the EGFR activates signalling cascades leading to cell proliferation, angiogenesis and inhibition of apoptosis, the EGFR represents an attractive target in cancer therapy. In GBM which is the most common primary central nervous system tumour in adults, the EGFR is overexpressed in about 40 to 50% of cases, and almost half of these co-express the mutant receptor subtype EGFRvIII. This EGFR variant is constitutively activated, and thereby may contribute to the aggressive and refractory course of GBM which is associated with a median survival of only 40 to 60 weeks from diagnosis. Various trials are ongoing focusing on EGFR and EGFRvIII as new therapeutic targets in GBM. Anti-EGFR monoclonal antibodies (MAbs), e.g. cetuximab, and tyrosine kinase inhibitors (TKIs), e.g. erlotinib and gefitinib, are the most advanced in clinical development. Several trials are investigating MAbs or TKIs in combination with other agents such as inhibitors of the mammalian target of rapamycin. Other still preliminary approaches targeting the EGFR are small interfering RNA, antisense RNA and ribozymes, which lead to degradation of EGFR mRNA. Further studies are needed to define their clinical potential, to identify biological predictors of response and thus to characterize subgroups of patients who will benefit from treatment with these new agents.