Current Medicinal Chemistry (v.18, #2)
Development of RET Kinase Inhibitors for Targeted Cancer Therapy by L. Mologni (162-175).
RET (Rearranged during Transfection) is a transmembrane tyrosine kinase expressed in central and peripheral nervous system and neural crest-derived cells and acts as a co-receptor of GDNF family neurotrophic factor in complex with GRFand#945; family proteins. RET protein comprises an extracellular portion with four cadherine-like domains and a cysteine- rich region important for intermolecular interactions; a hydrophobic transmembrane domain; an intracellular part comprising the juxtamembrane domain with regulatory function and the catalytic domain that phosphorylates the tyrosine residues of substrates. RET is involved in the development of enteric nervous system and renal organogenesis during embryonic life. Mutations of RET are associated to a subset of colorectal cancer and are commonly found in hereditary and sporadic thyroid cancer. Activating point mutations in the cystein-rich or the kinase domain of RET cause multiple endocrine neoplasia type 2 (MEN2), a group of familial cancer syndromes characterized by medullary thyroid carcinoma, pheochromocytoma, parathyroid hyperplasia and ganglioneuromatosis of the gastroenteric mucosa. Rearranged forms of RET (termed RET/PTC) are detected in the majority of papillary thyroid carcinomas (PTC). At present, the therapeutic treatment available for these pathologies is the total or partial surgical removal of thyroid, associated with radio-iodine therapy or chemotherapy: despite widespread use of multimodality treatment, survival rates have not improved much in the past few decades, which suggests that new treatment options should be explored. Several small-molecule inhibitors of RET kinase activity have been described in the last decade, some of which are currently undergoing clinical evaluation. Here, I review the large preclinical effort to the development of specific RET inhibitors, including medicinal chemistry analyses that may help refine potency and selectivity of future RET-targeted inhibitors.
Diagnostic and Therapeutic Use of Membrane Proteins in Cancer Cells by D. Grimm, J. Bauer, J. Pietsch, M. Infanger, J. Eucker, C. Eilles, J. Schoenberger (176-190).
As proteomics technologies develop, increasing number of membrane-associated proteins specific for cancer cells are being discovered. These proteins are of great interest, particularly because they are rich in targets for antibodies. Amongst them candidate biomarkers for early tumor diagnosis, prognosis and treatment have been detected. The suitability of several membrane-associated proteins as targets for drugs or antibodies has already been tested in preclinical and clinical studies. The results were encouraging in some cases, but not in all. They demonstrate that each type of tumor has its specific and#x201C;Achilles heeland#x201D;, and that suitable targets of cancer diagnosis and therapy must be found for each kind of neoplasm. This implies that membrane-associated proteins for each type of tumor cell need to be investigated. This review describes the current technologies of membrane protein characterization in a first part and subsequently summarizes the membrane associated proteins currently being tested as targets for diagnosis and treatment in breast, prostate, thyroid, and colon cancer. Their function will be explained and their role in tumor biology will be discussed.
The Role of Survivin for Radiation Oncology: Moving Beyond Apoptosis Inhibition by F. Rodel, S. Reichert, T. Sprenger, U. S. Gaipl, J. Mirsch, T. Liersch, S. Fulda, C. Rodel (191-199).
Alterations in the expression of apoptosis-related proteins, like the inhibitor of apoptosis (IAP) protein family, display a pivotal pathway by which cancer cells acquire resistance to therapeutic treatment. Among this family, survivin, the smallest and structural unique member, deserves growing attention due to its universal over-expression in human tumors, and its prominent role in disparate networks of cellular division, intracellular signaling and apoptosis. Several preclinical studies have demonstrated that targeting survivin expression by the use of small interfering RNAs, dominant negative mutants, antisense-oligonucleotides and small molecule repressors sensitized tumor cells towards chemotherapy and irradiation and reduced tumor growth potential. Due to these properties, survivin has been proposed as a molecular target for anticancer therapies. Recent studies further revealed that radio-sensitization achieved by survivin inhibition seems to be multifaceted and involves caspase-dependent and caspase-independent mechanisms. In general, an enhanced rate of apoptosis, and pronounced cell cycle arrest have been observed. More recently, a hampered DNA-damage response has been noted, indicating a distinct role of the protein in radiation-induced double strand break repair. These properties were linked to a nuclear import and physical interrelationship with members of the DNA-DSB repair machinery such as phospho-histone H2AX and DNA dependent Protein Kinase (DNA-PKcs). The applicability of survivin-driven strategies in clinical practice is currently under investigation as the first survivin inhibitors successfully entered phase I/II trials. Although these trials do not include radiation therapy at present, survivin inhibitors may represent a novel type of molecular antagonists to improve the effectiveness of radiation therapy or chemoradio- therapy.
Role of Natural Killer Cell Activity in the Pathogenesis of Endometriosis by Justyna Sikora, Aleksandra Mielczarek-Palacz, Zdzislawa Kondera-Anasz (200-208).
Natural Killer (NK) cells are cytotoxic effector lymphocytes with the ability to lyse target cells in a major histocompatibility complex (MHC) class I-independent manner and without the need for prior antigen exposure. Data strongly suggested that NK cells play an important role in human reproduction and disturbance in their function can favor development of the gynecological disorders. In our study the role of NK cells in pathogenesis of endometriosis is reviewed and summarized from available literature. Endometriosis is related to a defect of NK cell cytotoxicity function in the ability to eliminate endometrial cells in ectopic sites. Alternations of the innate immunity mediated by NK cells may promote impairments or disrupt functions of adaptive immunity, which can contribute to development and progression of endometriosis and infertility associated with endometriosis. Aberrant immune responses by NK cells in affected women may represent risk factors for endometriosis and the repaired function can be a new treatment target of the affected women.
The Toxicogenetics of Antirretroviral Therapy: The Evil Inside by M del M. Gutierrez, M G. Mateo, F. Vidal, P. Domingo (209-219).
The most important factor limiting the success of an antiretroviral therapy regimes is toxicity. Toxicity can depend on a number of factors; some of these are intrinsic to the host and may not only affect the latter's outward appearance, but also determine the intensity these toxic effects may reach. The former is exemplified by idiosyncratic or hypersensitivity reactions, whereas the latter is usually appreciated in metabolic disturbances or fat redistribution syndromes. Some of the determinants of antiretroviral toxicity are genetic in origin and have been the subject of intense study in recent years. Some of these are linked to a single nucleotide polymorphism (SNP), whereas others depend on a complex interaction between multiple genes variations. One of these tests (HLA B*5701) is now being applied in clinical practice and widely used to prevent the risk of hypersensitivity reactions to abacavir. Many other genetic determinants of antiretroviral drug toxicity have been suggested as an explanation for nucleoside analogue toxicity; these include lactic acidosis, peripheral neuropathy and pancreatitis, and have also been suggested as a potential basis for the non-nucleoside toxicity derived from immunogenetic factors involved in nevirapine hypersensitivity to SNPs in efavirenz enzyme metabolism, amongst other things. Metabolic toxicity, mainly due to protease inhibitors (PIs) is far more complex and depends on the interaction of various genes. The same seems to be true for fat redistribution syndromes and atherosclerosis, although a clear picture of the genetic factors operating in these syndromes is yet to emerge. The ultimate goal of pharmacogenetics is to customize antiretroviral therapy by identifying the genes that can maximise efficacy whilst helping avoid known side effects of antiretroviral drugs.
Computational Insights into Binding of Bisphosphates to Farnesyl Pyrophosphate Synthase by K. Ohno, K. Mori, M. Orita, M. Takeuchi (220-233).
Bisphosphonates (BPs) are the most widely used and effective treatment for osteoporosis and Paget's disease. Non-nitrogen containing BPs (non-N-BPs), namely etidronate, clodronate, tiludronate, as well as nitrogen-containing BPs (N-BPs), namely pamidronate, alendronate, ibandronate, risedronate, zoledronate and minodronate have been launched on the market to date. N-BPs act by inhibiting the enzyme farnesyl pyrophosphate synthase (FPPS), and several crystal structures of complexes between FPPS and N-BPs have been revealed. Understanding the physical basis of the binding between protein and small molecules is an important goal in both medicinal chemistry and structural biology. In this review, we analyze in detail the energetic basis of molecular recognition between FPPS and N-BPs. First, we summarize the interactions between ligands and proteins observed in N-BPs-FPPS complexes in the Protein Data Bank (PDB). Second, we present an interaction energy analysis on the basis of full quantum mechanical calculation of FPPS and N-BP complexes using the fragment molecular orbital (FMO) method. The FMO result revealed that not only hydrogen bond and electrostatic interaction but also CH-O and and#x3C0;-and#x3C0;interaction with FPPS are important for N-BP's potency. Third, we describe a binding site analysis of FPPS on the basis of the inhomogeneous solvation theory which, by clustering the results from an explicit solvent molecular dynamics simulation (MD), is capable of describing the entropic and enthalpic contributions to the free energies of individual hydration sites. Finally, we also discuss the structure-activity relationship (SAR) of the series of minodronate derivatives.
Targeting the Nogo Receptor Complex in Diseases of the Central Nervous System by C. L. McDonald, C. Bandtlow, M. Reindl (234-244).
After injury to the central nervous system intrinsic factors such as myelin associated inhibitory factors inhibit cellular and axonal regeneration resulting in permanent disability. Three of these factors (Nogo-A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein) bind to a common receptor: the Nogo-66 receptor (NgR1). NgR1 is expressed mainly on neurons and is usually associated in a trimolecular complex. The second member of the complex, LINGO-1, is often connected to NgR1 function and is further found to function independently as a negative regulator of oligodendrocyte proliferation and differentiation. The third member of the NgR complex is either the p75 neurotrophin receptor, TROY, or an as yet unidentified co-receptor. Targeting of factors contained in this complex has been described to lead to the promotion of neurite outgrowth, oligodendrocyte proliferation and differentiation and inhibition of cell death. In the current review, we aim to describe the mechanisms of action of the chemical and biological compounds used in targeting NgR1 and LINGO-1. This will be achieved using three examples: blocking of ligand binding to NgR1 in treatment of spinal cord injury, antibody-mediated inhibition of LINGO-1 to promote oligodendrocyte differentiation in multiple sclerosis, and the use of soluble NgR1 to sequester Abeta peptide in the periphery in Alzheimer's disease.
Inflammatory and Neurodegenerative Pathways in Depression: A New Avenue for Antidepressant Development? by M. Catena-Dell'Osso, C. Bellantuono, G. Consoli, S. Baroni, F. Rotella, D. Marazziti (245-255).
The latest advancement in neurobiological research provided an increasing evidence that inflammatory and neurodegenerative pathways play a relevant role in depression. Preclinical and clinical studies on depression highlighted an increased production of inflammatory markers, such as interleukin (IL)-1, IL-6, tumor necrosis factor-and#x3B1; and interferon- and#x3B1;and and#x3B3;. On the other hand, acute and chronic administration of cytokines or cytokine inducers were found to trigger depressive symptoms. According to the cytokine hypothesis, depression would be due to a stress-related increased production of pro-inflammatory cytokines that, in turn, would lead to increased oxidative and nitrosative brain damage and to indoleamine 2,3 dioxygenase (IDO) induction, with production of tryptophan (TRP) catabolites along the IDO pathway (TRYCATs) and consequent reduced availability of TRP and serotonin (5-HT). Cytokines would also play a role in the onset of the glucocorticoid resistance, underlying the overdrive of the hypothalamic-pituitary-adrenal axis. Therefore, the activation of the inflammatory and neurodegenerative pathways would lead to the brain damage observed in depression through both reduced neurogenesis and increased neurodegeneration. Besides the 5-HT system, other targets, possibly within the Iand#38;ND pathways, should be considered for the future treatment of depression: cytokines and their receptors, intracellular inflammatory mediators, IDO, TRYCATs, glucocorticoid receptors, neurotrophic factors may all represent possible therapeutic targets for novel antidepressants. In addition, it should be also clarified the role of the existing antiinflammatory drugs in the treatment of depression, and those compounds with the anti-inflammatory and anti-oxidative properties should be examined either as monotherapy or adjunctive therapy. In conclusion, the molecular inflammatory and neurodegenerative pathways might provide new targets for antidepressant development and might be crucial to establish a rational treatment of depression aimed, hopefully, to its causal factors.
Use of Antimicrobial Peptides Against Microbial Biofilms: Advantages and Limits by Giovanna Batoni, Giuseppantonio Maisetta, Franca Lisa Brancatisano, Semih Esin, Mario Campa (256-279).
The formation of surface-attached cellular agglomerates, the so-called biofilms, contributes significantly to bacterial resistance to antibiotics and innate host defenses. Bacterial biofilms are associated to various pathological conditions in humans such as cystic fibrosis, colonization of indwelling medical devices and dental plaque formation involved in caries and periodontitis. Over the last years, natural antimicrobial peptides (AMPs) have attracted considerable interest as a new class of antimicrobial drugs for a number of reasons. Among these, there are the broad activity spectrum, the relative selectivity towards their targets (microbial membranes), the rapid mechanism of action and, above all, the low frequency in selecting resistant strains. Since biofilm resistance to antibiotics is mainly due to the slow growth rate and low metabolic activity of bacteria in such community, the use of AMPs to inhibit biofilm formation could be potentially an attractive therapeutic approach. In fact, due to the prevalent mechanism of action of AMPs, which relies on their ability to permeabilize and/or to form pores within the cytoplasmic membranes, they have a high potential to act also on slow growing or even non-growing bacteria. This review will highlight the most important findings obtained testing AMPs in in vitro and in vivo models of bacterial biofilms, pointing out the possible advantages and limits of their use against microbial biofilm-related infections.
Peroxynitrite-Driven Mechanisms in Diabetes and Insulin Resistance the Latest Advances by K. Stadler (280-290).
Since its discovery, peroxynitrite has been known as a potent oxidant in biological systems, and a rapidly growing body of literature has characterized its biochemistry and role in the pathophysiology of various conditions. Either directly or by inducing free radical pathways, peroxynitrite damages vital biomolecules such as DNA, proteins including enzymes with important functions, and lipids. It also initiates diverse reactions leading eventually to disrupted cell signaling, cell death, and apoptosis. The potential role and contribution of this deleterious species has been the subject of investigation in several important diseases, including but not limited to, cancer, neurodegeneration, stroke, inflammatory conditions, cardiovascular problems, and diabetes mellitus. Diabetes, obesity, insulin resistance, and diabetes-related complications represent a major health problem at epidemic levels. Therefore, tremendous efforts have been put into investigation of the molecular basics of peroxynitrite-related mechanisms in diabetes. Studies constantly seek new therapeutical approaches in order to eliminate or decrease the level of peroxynitrite, or to interfere with its downstream mechanisms. This review is intended to emphasize the latest findings about peroxynitrite and diabetes, and, in addition, to discuss recent and novel advances that are likely to contribute to a better understanding of peroxynitrite-mediated damage in this disease.
Food Matrix Affecting Anthocyanin Bioavailability: Review by M. Yang, S. I. Koo, W. O. Song, O. K. Chun (291-300).
Anthocyanins, abundant in deep-colored fruits and vegetables, have received considerable attention due to their potential health benefits. However, the bioavailability of anthocyanins is relatively low compared to that of other flavonoids. While previous reviews focused on the absorption, metabolism and excretion of anthocyanins, little information is available on the effects of food matrix on anthocyanin bioavailability, particularly food matrices of the usual diet. The present review includes the recent studies on interactive effects of anthocyanins and certain food components. Evidence suggests that the bioavailability of anthocyanins varies markedly depending on food matrices, including other antioxidants and macronutrients present in foods consumed, which consequently affects the absorption and antioxidant capacity of anthocyanins. Further studies are needed to gain insight into the mechanisms underlying the interactive effects of anthocyanins and food components in their bioavailability and antioxidant capacity of anthocyanins at the physiological level.
Regulatory Mechanisms of Calcineurin Phosphatase Activity by R. E.A. Musson, N. P.M. Smit (301-315).
Calcineurin (protein phosphatase 3, Cn) is best known for its central position in Ca2+-dependent T-cell signaling. Interest in calcineurin has, however, conserved its momentum as new Ca2+-dependent pathways have been steadily surfacing in several other cell types, such as brain, heart, skin cells and beta pancreatic cells, and Cn appears to serve as a central controller of stress, immune response, and cellular proliferation and differentiation. Calcineurin is the principal target of the immunosuppressive drugs cyclosporin A (CsA) and tacrolimus (TRL). Therapy based on these immunosuppressants has markedly reduced the incidence of transplant rejection in allograft recipients. In addition, these drugs have proven very useful for patients suffering from chronic inflammatory skin conditions. Unfortunately, their application is somewhat limited by a broad spectrum of toxic side-effects, affecting several organ systems. This calls for enhancements in the design of this class of immunosuppressants. An intricate constellation of regulatory systems allows for precise modulation and adaptation of calcineurin activity in vivo. The last few years have been very fruitful in elucidating several long-standing issues regarding the binding patterns of substrates and inhibitors to Cn. This new knowledge may enable more precise manipulation of the Ca2+-calcineurin pathway in the near future, preferably targeted towards one specific substrate or cell system. In this review, we will discuss the factors and mechanisms underlying calcineurin activity regulation and their exploitation in recent approaches towards better immunosuppressants.