Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 10, Issue 1, 2010

Cancer metastasis is the most life threatening event in patients with solid tumours. As a result, understanding the underlying mechanisms and searching for factors that control the metastatic spread of cancer cells are critical in the area of cancer research. Furthermore, agents that interfere with the metastasis of cancer cells are of great value in cancer treatment. Of the complex nature of cancer metastasis, a few events are key to the metastatic process, namely, loss of cell adhesiveness (to each other), breakdown of the basement membrane and extracellular matrix, intravasation and extravasation, angiogenesis and lymphangiogenesis. There are few factors that are as widely involved in the regulation of metastatic spread of cancer as hepatocyte growth factor (HGF, also known as scatter factor). Discovered in the nineteen eighties as a potent mitogen for hepatocyte and protein factor causing scatter of epithelial cells [1,2], HGF was soon found to be a power protein factor that stimulates the aggressiveness of cancer cells, from loss of cell-cell adhesion, increased invasiveness and motility of cancer cells, to being a powerful angiogenic and lymphangiogenic factor. The first article in the current issue summarises the main characteristics of the factor in cancer [3]. The broad and potential involved involvement of HGF in cancer has inspired a great deal of interest in targeting the factor and indeed its receptor, cMET. From the development of neutralising antibodies to both HGF and its receptor and the discovery of a complete antagonist and small molecule inhibitors, there are now multiple options in targeting the cytokine axis. In the current issue, the current status of cMET inhibitors, from the chemical structure to current preclinical and clinical studies, are comprehensively reviewed by Underiner et al [4], with an excellent article from Abounader’s group showing the impressive effect of one of the compounds [5]. The clinical implications for the HGF antagonist are clear evident from Matsumoto's work [6]. New methods of targeting HGF and its receptor have been development, including the HGF activation inhibitors, HAI, and a most unexpected enzyme, matriptase-2 [7,8]. Not covered in this issue are some other technologies targeting HGF and cMET which may also have potential therapeutic implications in cancer, including small inhibitory RNA, non-specific inhibitors to HGF and inhibitor to the cMET downstream signalling pathways. As evident from this special issue and the rapid progress in this area, one cannot resist an expectation that some of the anti-HGF/cMET agents will eventually find their way into clinical practice, particularly in the treatment of advanced cancer. It is further hoped that the current issue will provide a valuable tool and reference for industry, clinical and laboratory research into this fascinating area of cancer research.

Hepatocyte growth factor (HGF) and it's receptor, cMET, have become the focus on intense scrutiny since its discovery in the late 1980s [1, 2] as regards it role in cancer. HGF is now known to be a potent morphogen that can regulate tissue and organ regeneration and modulate cell morphology, it is a motogen that can stimulate cell motility and migration, and is a mitogen able to regulate cell growth and death and as an angiogenic factor [3]. HGF is can induce both angiogenesis and lymphangiogenesis [3a; 4]. That HGF and cMET have such a diversity of functions has led to intense interest in the clinical setting due to their potential in their prognostic aspect and therapeutic implications as imaging tools. This issue will focus on recent work that shows strong indications for the value of HGF and cMET in clinical settings.

The scatter factor/hepatocyte growth factor (HGF)-c-Met axis is involved in the malignant phenotype of various tumor types via activation of a wide range of autocrine and paracrine processes. Autocrine activation of tumor cell c-Met receptors enhances tumor cell proliferation, angiogenesis, invasion/metastasis and resistance to apoptosis and cytotoxic therapies. In addition, tumor and stroma cell-derived HGF functions as a potent angiogenic factor. Therefore, the HGF-c-Met axis is critically involved in multiple facets of normal cellular growth and homeostasis and activated in a dysregulated manner in a variety of cancers. Consequently, inhibiting the HGF-c- Met axis would be anticipated to have potent anti-tumor effects in many cancers through multiple complimentary mechanisms including increased sensitivity to current cytotoxic chemo-and radiotherapies. The acceptance of c-Met as a tractable target for cancer therapy has fostered intensive drug discovery efforts across the pharmaceutical industry. This research has led to 20 published crystal structures (with and without ligands) that revealed two distinct binding modes for ATP-competitive inhibitors: Type I ligands which assumes a U shape geometry through interactions with both hinge and activation loop residue Y1230, and Type II ligands which adopt a more extended orientation, either binding a conventional DFG-out conformation or protein conformations with varying degrees of ‘DFG-out’ character. Nearly a dozen small molecule c-Met inhibitors have entered human clinical trials ranging from Type I inhibitors solely selective for c- Met to Type I inhibitors with broader kinase activities to Type II inhibitors with “spectrum selective” kinase activity. The identification, profiles and properties of these clinical candidates are summarized in this review.

The receptor tyrosine kinase, c-Met and its ligand hepatocyte growth factor (HGF) are important regulators of malignancy in human cancer including brain tumors. c-Met is frequently activated in brain tumors and has emerged as a promising target for molecular therapies. Recently, an orally bioavailable small molecule kinase inhibitor of c-Met (SGX523) was developed by SGX Pharmaceuticals. We tested the effects of this inhibitor on c-Met brain tumor cell activation, c-Met-dependent malignancy, and in vivo glioma xenograft growth. SGX523 potently inhibited c-Met activation and c-Met-dependent signaling at nanomolar concentrations in glioma cells, primary gliomas, glioma stem cells and medulloblastoma cells. SGX523 treatment inhibited c-Met-dependent brain tumor cell proliferation and G1/S cell cycle progression. SGX523 also inhibited brain tumor cell migration and invasion. Furthermore, systemic delivery of SGX523 via oral gavage to mice bearing orthotopic human glioblastoma xenografts led to a significant decrease of in vivo tumor growth. These studies show that c-Met activation and c-Met-dependent brain tumor cell and stem cell malignancy can be inhibited by small molecules. The study also shows for the first time that oral delivery of a small molecule kinase inhibitor of c-Met inhibits intracranial tumor growth. These findings suggest that targeting c-Met with small molecule kinase inhibitors is a promising approach for brain tumor therapy.

We identified NK4, the N-terminal and four kringle domains of hepatocyte growth factor (HGF), as a specific inhibitor of HGF. NK4 binds to the Met/HGF receptor, but does not activate the Met receptor, thereby competitively inhibiting the HGF-Met pathway. Independent of its inhibition of HGF-Met, NK4 acts as an angiogenesis inhibitor. The angioinhibitory action of NK4 is mediated by perlecan, a multidomain proteoglycan involved in vascular basement membrane assembly. The extracellular binding of NK4 to perlecan inhibits cell-associated assembly of fibronectin, and the impaired fibronectin assembly suppresses integrin-dependent angiogenic responses, i.e., endothelial cell proliferation, migration and tube formation. NK4 or an NK4-like fragment is generated by proteases expressed in inflammatory cells, suggesting regulation of physiological or pathological processes by NK4 or NK4-like fragments. In a variety of cancer models, NK4 exhibited anti-cancer effects due to its bifunctional characteristics, including inhibition of invasion and metastasis, inhibition of angiogenesis-dependent tumor growth, and promotion of survival. Several lines of strategies and different molecules that inhibit the HGF-Met pathway have been developed, including small molecular inhibiters of Met tyrosine kinase. The biological action of NK4 as an angiogenesis inhibitor has definite advantages over other molecules. In addition to the well-acknowledged role of HGF-Met in cancer invasion and metastasis, recent studies indicate that activation of the HGF-Met pathway makes tumor-initiating cells invasive and resistant to chemical and radiation therapy. Treatment with NK4 could offer a new therapeutic option for the inhibition of cancer metastasis and growth, and better outcomes for cancer patients.

Hepatocyte growth factor (HGF) plays a plethora of roles in the progression of many invasive and metastatic cancers. The interaction between tumour cells and their surrounding stromal environment remains a crucial factor governing tumour invasion and metastasis. HGF is primarily synthesised by stromal fibroblasts as an inactive precursor known as pro-HGF. A number of proteases have demonstrated the ability to convert pro-HGF into the biologically active form of HGF, although the two main factors responsible are HGF activator (HGFA) and matriptase. The HGF activation inhibitors (HAI-1 and HAI-2) are two novel Kunitz-type serine protease inhibitors that regulate HGFA and matriptase activity to govern the influence of HGF within the body. Deregulation of HAI expression can lead to shift in the HGF activation/inhibition balance ratio in favour of enhanced HGF production. Therefore, these HGF activation inhibitors may have a direct bearing on cancer invasion and metastasis. This review examines the accumulating evidence on the emerging role and therapeutic potential of HAI-1 and HAI-2 in cancer.

Metastasization is an undesirable process in cancer development and may represent the most critical factor in deciding patient prognosis. Organ specificity of the metastasis process suggests the importance of the paracrine factors: one of the most potent paracrine regulators of tumor cell migration is hepatocyte growth factor/scatter factor (HGF/SF). Because the liver-specific growth factor is HGF, its receptor c-Met expression might play a critical role in metastasization to the liver. Activation of HGF/c-Met signaling has been shown to promote cancer cell invasiveness and trigger metastasis though direct involvement of the angiogenic pathway. Given the importance of aberrant HGF/c-Met signaling, several different therapeutic strategies aimed at inhibiting the pathway have been developed and are currently being evaluated in clinical trials. Among these agents, NK4 and AM102 were introduced as HGF inhibitors, and PHA-665752 and Su11274 as c-Met inhibitors and are under study in clinical trials. Further, clinical experience-based study to apply the accumulation of biological knowledge concerning HGF/c-Met to the surgical field is presented.

Matriptase-2 is a newly identified member of the Type II Transmembrane Serine Protease (TTSP) family. The expression profile of many members of this family of proteases is frequently altered in cancerous cells and tissues and a number of TTSPs have been linked to cancer progression and development. Matriptase-2 is structurally similar to matriptase-1, a TTSP which has gained recent interest due to its potential to enhance the aggressive nature of cancer cells and its links with a variety of human cancers. Recently, matriptase- 2 has been functionally linked to the regulation of iron metabolism; however, there is also evidence to suggest that, as with other members of the TTSPs, matriptase-2 may have a role in cancer development and progression. This article reviews the current literature on matriptase-2, together with its potential roles in physiological and disease states particularly focusing on cancer.

Barminomycin is a member of the anthracycline class of anticancer agents and was originally discovered as a pink/red complex with DNA and RNA and named SN-07. The chromophore was subsequently separated from the nucleic acids by nuclease digestion and contained the four-membered anthraquinone ring system characteristic of anthracyclines, but with an unusual eight membered ring that contained a carbinolamine which readily interconverted to an imine. The imine form is analogous to the formaldehyde-activated form of other anthracyclines such as doxorubicin. The imine form confers exceptional activity to barminomycin which is 1,000-fold more cytotoxic than doxorubicin. Barminomycin rapidly forms adducts with DNA, reacting with the exocyclic amino group of guanine residues and with high selectivity for 5'-GC-3' sequences. The coupling to DNA appears to be identical to the N-C-N aminal linkage formed between doxorubicin and DNA where the carbon derives from formaldehyde for doxorubicin-DNA adducts, whereas this “activated carbon” is an inherent component of the imine group in the eight membered ring of barminomycin. Although the linkage of both drugs to DNA appears to be identical, barminomycin-DNA complexes are essentially irreversible compared to the labile doxorubicin-DNA adducts which have an in vitro (purified DNA) half-life of 25 h at 37 °C. A 3D model of the barminomycin-DNA complex has been defined from 307 NOE distance constraints. The enhanced stability of barminomycin-DNA adducts appears to be due primarily to protection of the aminal linkage from hydrolysis and this has provided insight into the design of new anthracycline derivatives with enhanced stability and activity. Strategies for harnessing the extreme reactivity and activity of barminomycin are also presented.

Bisdioxopiperazine compounds, including ICRF-154 and razoxane (ICRF-159, Raz), are anticancer agents developed in the UK specifically targeting tumor metastases. Further two bisdioxopiperazine derivatives, probimane (Pro) and MST-16, have been synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, PR China after 1980. Anticancer activities and mechanisms of Pro and MST-16 compared with Raz, especially for antiproliferative and antimetastatic effects in vivo and in vitro, have been systematically evaluated in this lab as well as by other authors in China. Novel molecular mechanisms especially relating to the inhibition of tumor metastasis between probimane and razoxane have been especially explored and explained, including pathways of inhibitions against calmodulin, sialic acid, lipoperoxidation, fibrinogen, cell-movement and the cell-cycle arrest. The distributions and excretions of 14[C]-Pro in mice have been carefully monitored long before for explaining the relationship of pharmacological data between in vitro and in vivo evaluations. Pro is more soluble in water and more strongly active against tumors than Raz. In our point of view, Pro seems to inherit and retain most of the targets and pathways of other bisdioxopiperazine compounds currently in use and is cytotoxically more potent than the rest of bisdioxopiperazine compounds. Therefore, there is a great potential and significance for further investigations.

With the advent of the modern cancer treatment, survival rates have improved substantially raising new concerns towards quality of life issues such as future fertility and offspring welfare. Cancer researchers are expanding their focus beyond survival and recurrence rates to include maximization of fertility potential for young cancer patients. Despite promising cure rates with chemotherapy, studies have shown it to act as a double edge sword by adversely affecting male fertility. Chemotherapeutic agents act by hindering rapidly proliferating cells, hence exerting their gonadotoxic effect. The extent of damage to germ cells and eventual fecundity depends on the class of chemotherapeutic agent, dosage, spermatogenetic stage targeted as well as the original pretreatment fertility potential of the patient. In this review, we provide a contemporary overview of the effects of anticancer agents on male fertility. Gonadotoxicity caused by these agents will be analyzed followed by the contemporary measures to preserve future fertility. Both established and potential strategies of fertility preservation will be discussed with emphasis on cryopreservation and its efficacy in conjunction with assisted reproductive technologies in addition to the current recommendations for this preservation modality. Finally, contemporary research on the welfare of offspring of cancer survivors will be reviewed.