Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 12, Issue 1, 2012

The journal Anti-Cancer Agents in Medicinal Chemistry has recently received its first impact factor of 3.144. I am sure this will encourage very high quality manuscript submissions going forward. I would like to take this opportunity to thank the authors for their excellent contributions, and the reviewers and Editorial Board Members for their precious assistance. I would like also to thank Ms. Madiha Zahoor and the entire staff of the Editorial Office of Bentham Science for their kind assistance. As Editor-in-Chief, I wish Anti-Cancer Agents in Medicinal Chemistry to become an expert forum to convey the latest research in medicinal chemistry and rational drug design for the discovery of new anti-cancer agents. In addition to review articles, Anti-Cancer Agents in Medicinal Chemistry is now publishing research papers which, like all manuscripts, are subjected to peer reviewing. Many Hot Topic Issues aim at providing readers with the latest developments on areas which are crucial for the progress of new therapeutic avenues. A part of the first 2012 Issue, proposed by J. Eswaran, is thematic and focuses on targeting G protein and phosphorylation dependent signalling molecules for anticancer therapy. In addition to a large number of general reviews and research articles in various exciting areas, the following thematic issues are also planned for the year 2012: novel therapeutic approaches for human cancers, recent developments of molecular targeted anti-cancer agents, new anti-cancer drugs from nature medicine and contrast agents in bio-medical imaging. I would like Anti-Cancer Agents in Medicinal Chemistry to be considered an indispensable source of knowledge by all scientists working in the field and to open up future prospects for them. I wish an excellent and fruitful year 2012 to the readers and members of the Editorial Board.

G-protein and phosphorylation dependent signalling network are the major signalling pathways that control several fundamental cellular processes. Therefore understanding the biology and the molecular mechanism of these molecules allow us to identify possible drug targets. Although there has been an incredible research focus on understanding the onset and progression of cancer, the search still continues across various avenues to come up with novel therapeutics and improvised strategies to combat cancer. Here, the aim of this hot thematic issue is to highlight emerging G-protein and phosphorylation dependent signalling molecules that are potential anticancer drug targets as well as “drug like” molecule development strategies. During cancer invasion, the first line of defence is conceded when the tumour associated antigens are misrecognised as self-associated entities. This happens mainly because the host T cells that tackle the tumoral cells through specific immune responses accidently results in uninhibited tumour cell progression. Therefore, understanding the mechanism of immune system recognition and elimination of “cancer triggers” at the molecular level through immunosurveillance is essential for the development of novel, anti-cancer strategies. This concept is extensively discussed by Escors and coworkers where they detail how the constitutively activated MAP kinase, NF-κB and Toll like receptor pathways provide effective mode of cancer immunotherapy. The use of constitutive activators of TLR signalling, NF-κB and MAPK pathways appears promising in preclinical models enabling the possibility of this line of attack to be complementary to the much prevalent but classical current radio and chemotherapies. The identification of tumor associated antigens (TAAs) and the increasing knowledge of Toll-like receptors and other signal transduction pathways provide the basis for this approach, and Arce et al discuss this in detail in their article. Using kinase inhibitors as anticancer agents have been the most popularised approach. However recent studies from various groups using structural genomics and other approaches have provided in depth insight into the molecular mechanism and regulation of tyrosine dephosphorylating PTPases. The comprehensive overview provided by Tremblay and colleagues in the review titled ‘Impact of oncogenic protein tyrosine phosphatases in cancer’ offer extensive account of various PTPs that are deregulated in specific types of cancers and critical rationale that enables PTPs as cancer targets. In addition, Hardy et al also provides functional overview of broad array of PTP family members, with their biological significance in oncology, and how recent structural and functional characterisation enhances the understanding of PTP family molecular mechanism and substrate specificity. Apart from the kinases and phosphatases, another central player, the GTPases function as integral components in several signalling cascades. More interestingly, the emerging atypical GTPases family with altered domain architecture, tertiary structures, and guanine nucleotide binding properties highlight the versatile nature and diversity found in the fundamental mechanism such as GTP hydrolysis. Soundararajan et al review the members of this family and focuses mainly on two families of atypical Ras GTPases, the RGK GTPases and centaurin isoforms, which modulate various signalling nexus of the cancer therapy targeted PI3 kinase-AKT-mTOR signalling pathway. The role of RGKs in cyctoskeletol remodelling and the biological function of centaurin in calcium signalling and cancer development and neuronal functions is discussed elaborately. The unusual catalytic motifs and structural elements are discussed in the context of classic GTPase, H-Ras. In summary, this review provides comprehensive report on the recent progress in the atypical GTPases field prompting the field to focus on “contemporary” functions of the atypical GTPase domain. In addition to the identification of “druggable signalling modulators”, developing novel anticancer agents is also proved to be an integral component of cancer therapeutics development. Recent focus involving more systematic approach to screen phytochemicals using high throughput screening by cancer researchers have placed them as promising class of entities for alternative drug molecule development. Chitra Mandal and colleagues have discussed how natural products derived small molecules can be effectively used as specific anti-cancer agents that target signalling pathways. In this article, the authors categorize the extracts and their sources along with the possible mechanisms of action in cancer chemotherapy generating an excellent catalogue of compounds and signalling pathways they may interfere. Further, the anticancer agents derived from medicinal plants that exhibit remarkable chemo-preventive and anti-tumorigenic properties detailed in this review provides us convincing evidence for the tremendous potential these unexplored agents offer towards tackling apoptotic pathways in various cancer types. Another well-established, successful drug development concept is the fragment based drug design, which has been tested and proved to be effective over the past decade. Turnbull and Boyd in this issue systematically provide an overview of the principle, concept development, and screening techniques employed for fragment interaction detection. Identifying weak interaction between the fragment and the target molecule is identified as a challenge in this approach. Turnbull et al discusses the strengths and pitfalls of current arsenal of methodologies such as nuclear magnetic resonance (NMR), X-ray crystallography, surface plasmon resonance (SPR), thermal shift assay (TSA) and high concentration screening (HCS). Further, a comprehensive case study of inhibitor development using fragment based drug design approach for various targets including Aurora kinase, PDK1, Pin1, Bcl-2, Hsp90, PKB, CDK, uPA, BRAF kinase, BCR-Abl, Chk-1 and JAK2 is outlined highlighting the successful establishment of this approach. In keeping with that, there are several FBDDderived compounds now entering into various stages of clinical trial. Thus, Turnbull et al provides a timely, comprehensive overview on the application of fragment based drug design process that would expand the chemical diversity and druggable window of anti-cancer agents. In summary, the presented hot thematic issue brings forth unexplored target areas in the rapidly moving field of G-protein and phosphorylation dependent signalling, current drug screening strategies as well as naturally occurring anti-cancer agents.

Protein tyrosine phosphatases (PTPs) constitute a large family of enzymes that can exert both positive and negative effects on signaling pathways. They play dominant roles in setting the levels of intracellular phosphorylation downstream of many receptors including receptor tyrosine kinases and G protein-coupled receptors. As observed with kinases, deregulation of PTP activity can also contribute to cancer. This review will examine a broad array of PTP family members that positively affect oncogenesis in human cancer tissues. We will describe the PTP family, their biological significance in oncology, and how recent progress is being made to more effectively target specific PTPs. Finally, we will discuss the therapeutic implications of targeting these oncogenic PTPs in cancer.

The Ras GTPases are the founding members of large Ras superfamily, which constitutes more than 150 of these important class of enzymes. These GTPases function as GDP-GTP-regulated binary switches that control many fundamental cellular processes. There are a number of GTPases that have been identified recently, which do not confine to this prototype termed as “atypical GTPases” but have proved to play a remarkable role in vital cellular functions. In this review, we provide an overview of the crucial physiological functions mediated by RGK and Centaurin class of multi domain atypical GTPases. Moreover, the recently available atypical GTPase structures of the two families, regulation, physiological functions and their critical roles in various diseases will be discussed. In summary, this review will highlight the emerging atypical GTPase family which allows us to understand novel regulatory mechanisms and thus providing new avenues for drug discovery programs.

One of the major challenges in achieving effective anti-cancer immunotherapy is to counteract immunological tolerance. Most tumor-associated antigens (TAAs) are sensed as self. Hence, naturally occurring tolerance towards them has to be overcome. Fortunately, there is increasing evidence that anti-tumor immune responses occur and play a crucial role in the success of well-established anti-neoplastic therapies such as radiotherapy and chemotherapy. In fact, their effectiveness relies on signalling by pattern recognition receptors such as Toll-like receptors (TLRs). TLR signal transduction involves activation of a few well-known pathways, of which nuclear factor κB (NF-κB) and mitogen activated protein kinases (MAPKs) are possibly the best characterized. Therefore, constitutive activation of these pathways in immune cells can potentially enhance anti-tumor immunity, especially when targeted to professional antigen presenting cells (APCs) such as dendritic cells (DCs). Several strategies have been devised to test this hypothesis, including constitutive activation of TLRs, NF-κB and MAPKs (extracellular-signal regulated kinase (ERK), p38 and c-Jun kinase 1 (JNK1)). Activation of these pathways in mouse and human DCs has differential effects in immunogenicity and in many cases, enhanced antitumor immunity in pre-clinical models, establishing the basis for future clinical applications.

Over the past decade, fragment-based drug discovery has developed significantly and has gained increasing popularity in the pharmaceutical industry as a powerful alternative and complement to traditional high-throughput screening approaches for hit identification. Fragment-based methods are capable of rapidly identifying starting points for structure-based drug design from relatively small libraries of low molecular weight compounds. The main constraints are the need for sensitive methods that can reliably detect the typically weak interactions between fragments and the target protein, and strategies for transforming fragments into higher molecular weight drug candidates. This approach has recently been validated as series of compounds from various programs have entered clinical trials.

Natural products are important sources of anti-cancer lead molecules. Many successful anti-cancer drugs are natural products or their analogues. Many more are under clinical trials. The present review focuses on chemopreventive and anti-cancer activities of polar and non-polar extracts, semi purified fractions and pure molecules from terrestrial plants of India reported between 2005 and 2010 emphasizing possible mechanisms of action of pure molecules.

Besides the common issue of drug-resistance, the conventional approaches for cancer diagnostics and treatment are constantly challenged by poor selectivity and limited access to neoplastic cells, which not only lead to the dose-limiting effect on the tumor region, but also bring side-effects to healthy cells/tissues. In recent years, a novel strategy has arisen to target the vasculature of tumors for drugdelivery and molecular imaging, based on the success of anti-angiogenic therapy. In addition to being easily accessible, the endothelial cells of tumor vasculature are also genetically stable and thus do not develop drug-resistance, making them ideal targets for chemotherapeutics and biomedical imaging. Among various ligands identified so far, the Asn-Gly-Arg (NGR) tripeptide can specifically target the neovasculature via interaction with the aminopeptidase N (APN / CD13) receptor which is highly up-regulated in the membranes of endothelial tumor cells. NGR-directed drug delivery as well as molecular imaging have therefore been undergone development, and appear to be intriguing approaches in current cancer research. Herein we highlight some recent developments of the NGR peptide based cancer therapy including drug-delivery and imaging studies, with future perspectives. Some of these agents have been under clinical trials, indicating promising future for the NGR-based drugs.

Anaplastic thyroid cancer (ATC) is often incurable because it doesn't respond to radioiodine, radiotherapy or chemotherapy, and new therapeutic approaches are needed. Peroxisome proliferator-activated receptor-gamma (PPARg) gene and protein are present in ATC cells, and PPARg ligands inhibit cell proliferation, induce apoptosis, and also down regulate the invasive potential of ATC cells. Also, inhibitors of the Aurora serine/threonine kinases have antineoplastic effect on ATC cells in vitro and on ATC xenografts. Tyrosine kinases inhibitors are actually under evaluation for the treatment of ATC, for example imanitib or sorafenib. Other studies have focused on evaluating antiangiogenic agents for treatment of ATC. These agents include: combretastatin A4 phosphate, aplidin, PTK787/ZK222584, and human VEGF monoclonal antibodies (bevacizumab, cetuximab). Small-molecule adenosine triphosphate (ATP) competitive inhibitors directed intracellularly at epidermal growth factor receptor (EGFR)'s tyrosine kinase, such as erlotinib, or gefitinib are also under evaluation. The development of drugs that have multiple therapeutic targets and the utilization of multiple cancer-targeting agents are both emerging strategies for ATC treatment. For example, a preclinical study evaluated the activity of a dual inhibitor of EGFR and vascular endothelial growth factor (VEGF), NVP-AEE788, alone and in combination with paclitaxel for the treatment of ATC. Even if new therapeutic approaches against ATC are under development, more research is needed to finally identify therapies able to control and to cure this disease. The possibility of testing the sensitivity of primary ATC cells from each subject to different drugs could increase the effectiveness of the treatment in the next future.