Current Medicinal Chemistry - Volume 20, Issue 10, 2013

Fibroblast growth factor receptor-4 (FGFR4) is a tyrosine kinase with a range of important physiological functions. However, it is also frequently mutated in various cancers and is now generating significant interest as a potential therapeutic target. Unfortunately, biochemical characterization of its role in disease, and further evaluation as a drug target is hampered by lack of a specific inhibitor. We aimed to discover new inhibitors for FGFR4 ab initio using a strategy combining in silico, in vitro and cell-based assays. We used the homologous FGFR1 to calculate docking scores of a chemically-diverse library of approximately 2000 potential kinase inhibitors. Nineteen potential inhibitors and ten randomly- selected negative controls were taken forward for in vitro FGFR4 kinase assays. All compounds with good docking scores significantly inhibited FGFR4 kinase activity, some with sub-micromolar (most potent being V4-015 with an IC50 of 0.04 μM). Four of these compounds also demonstrated substantial activity in cellular assays using the FGFR4- overexpressing breast carcinoma cell line, MDA-MB453. Through immunoblot assays, these compounds were shown to block the phosphorylation of the FGFR4 adaptor protein, FGFR substrate protein-2α (FRS2α). The most potent compound to date, V4-015, suppressed proliferation of MDA-MB453 cells at sub-micromolar concentrations, activated the pro-apoptotic caspases 3/7 and inhibited cellular migration. While achieving complete selectivity of this compound for FGFR4 will require further lead optimization, this study has successfully identified new chemical scaffolds with unprecedented FGFR4 inhibition capacities that will support mechanism of action studies and future anti-cancer drug design.

Farnesylthiosalisylic acid (FTS) is a potent non-toxic anticancer drug that targets oncogenic and pathologically activated Ras. The mechanism of action of FTS is well understood. It interferes with the binding of activated Ras proteins to their escort chaperons and with Ras tethering to the plasma membrane. This agent has been evaluated successfully in phase II clinical trials of pancreatic and lung cancer patients. It is generally agreed that Ras proteins play an important role in cancer, but they also drive activation of the immune system. Therefore we hypothesized that inhibiting Ras might be beneficial in autoimmune and inflammatory conditions. Over the past decade we have extensively studied the effects of FTS in multiple animal models of such diseases. We were able to show potent anti-inflammatory properties of FTS in autoimmune disease models such as systemic lupus erythematous, antiphospholipd syndrome, Guillain-Barre syndrome, multiple sclerosis, and inflammatory bowel diseases. Its potential was also shown in type I and type II diabetes. Animal models of contact dermatitis, allergic inflammation, and proliferative nephritis were studied as well. We have also investigated the molecular mechanisms, signaling pathways, and inflammatory mediators underlying these conditions. In this review we summarize our (and others) published data, and conclude that FTS has great potential as a safe anti-inflammatory drug.

Cancer is the leading cause of death in economically developed countries and the second leading cause of death in developing countries. This global burden of cancer continues to increase largely because of the aging and growth of the world population. Although very much progress has been attained in the development of new therapies, there is a clear need of more efficient and selective antitumor drugs for the effective treatment of many types of cancer. Among the different strategies developed to create new antitumor drugs, pleiotropic non-genotoxic effectors have gained interest since this approach is less susceptible to known resistance mechanisms. The cell nucleus is the subcellular compartment where the genetic information and the transcription machinery reside and accordingly where numerous therapeutic agents efficiently work. Hence, nuclear-targeted drugs are expected to kill cancer cells more directly and efficiently. In this review, we discuss the potential of nuclear-targeted drugs as antineoplastic therapeutics and reason the benefits of the strategy to endow ribonucleases with cytotoxic properties based on its targeting into the nucleus.

The resistance of infectious bacteria to current antibiotics is a worldwide problem. Previous studies have demonstrated the efficacy of nanostructured molecules against pathogens as an innovative methodology for the development of novel drugs. Currently, 95% of properties limited pharmacies applicability such as low solubility, short half-life in the circulatory system, toxicity associated to controlled release and immunogenicity. Furthermore, nanobiotechnology provides a different perspective for modifying these properties and allows innovative drug development. In this context, this review aims to describe different methods, polymers, and drugs used to obtain and analyze nanostructures associated with antibiotics as an unconventional and innovative tool for bacterial control. Biotechnology provides a different perspective for modifying drug properties and allows innovative drug development. This review describes nanostructures in association with antibiotics as an unconventional and innovative tool for bacterial control.

Ion channel targeted drugs have always been related with either the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc. However, traditional channel blockers have multiple adverse events, mainly due to low specificity of mechanism of action. Lately, novel ion channel subtypes have been discovered, which gives premises to drug discovery process led towards specific channel subtypes. An example is Na+ channels, whose subtypes 1.3 and 1.7-1.9 are responsible for pain, and 1.1 and 1.2 – for epilepsy. Moreover, new drug candidates have been recognized. This review is focusing on ion channels subtypes, which play a significant role in current drug discovery and development process. The knowledge on channel subtypes has developed rapidly, giving new nomenclatures of ion channels. For example, Ca2+ channels are not any more divided to T, L, N, P/Q, and R, but they are described as Cav1.1-Cav3.3, with even newer nomenclature α1A-α1I and α1S. Moreover, new channels such as P2X1-P2X7, as well as TRPA1-TRPV1 have been discovered, giving premises for new types of analgesic drugs.

Thymidylate kinase (TMPK) is a key enzyme for pyrimidine synthesis that catalyzes the phosphorylation of thymidine 5’-monophosphate (dTMP) in the presence of ATP and Mg2+ to form thymidine 5’-diphosphate (dTDP), which is then converted to thymidine 5’-triphosphate (dTTP) by nucleoside-diphosphate kinase (NDK). TMPK has an important function in cell proliferation and its enzyme kinetics and related structures have been determined in various organisms. TMPK is well recognized as a potential drug target, with the most notable function being in the activation of anti-HIV nucleoside prodrugs. Recent studies have shown that TMPK is a validated target for antibiotic development against grampositive bacterium of Staphylococcus aureus. In addition, inhibition of human TMPK increases the potential of anticancer agent doxorubicin toward colon cancer cells regardless of p53 status. Following the rapid expanding knowledge on TMPKs and the rising interests in TMPKs as a drug target, in this review we try to describe current research on TMPKs in various organisms of eukaryotes, prokaryotes and viruses and to provide information for designing new potential inhibitors against TMPKs.

Benign prostatic hyperplasia (BPH) is a major health concern that is likely to have an increasing impact in line with the gradual aging of the population. BPH is characterized by smooth muscle and epithelial proliferation primarily within the prostatic transition zone that can cause a variety of problems for patients, the most frequent are the lower urinary tract symptoms. BPH is thought to involve in disruption of dihydrotestosterone (DHT)-supported homeostasis between cell proliferation and cell death, and, as a result, proliferative processes predominate and apoptotic processes are inhibited. Phytotherapeutic supplements, mainly based on Saw Palmetto-derived Serenoa Repens (SeR), are numerous and used frequently. Serenoa Repens reduces inflammation and decreases in vivo the androgenic support to prostatic cell growth. Furthermore, SeR stimulates the apoptotic machinery; however, data supporting efficacy is limited, making treatment recommendations difficult. Besides SeR, selenium (Se), an essential trace element mainly functioning through selenoproteins and able to promote an optimal antioxidant/oxidant balance, and lycopene (Ly), a dietary carotenoid synthesized by plants, fruits, and microorganisms with a strong antioxidant activity, has been shown to exert beneficial effects in prostate disease. SeR is frequently associated with Ly and Se, in order to increase its therapeutic activity in benign prostatic hyperplasia (BPH). It has been shown that the Ly-Se-SeR association has a greater and enhanced antiinflammatory activity that might be of particular interest in the treatment of BPH. The Ly-Se-SeR association is also more effective than SeR alone in reducing prostate weight and hyperplasia, in augmenting the pro-apoptotic Bax and caspase-9 and blunting the anti-apoptotic Bcl-2 mRNA. In addition, Ly-Se-SeR more efficiently suppresses the EGF and Vascular Endothelial Growth Factor (VEGF) expressions in hyperplastic prostates. Therefore, SeR particularly when combined with Se and Ly may have a greater potential for the management of benign prostate hyperplasia.

Although the renin-angiotensin system (RAS) is already an old acquaintance, there are often exciting discoveries that improve our knowledge of it and open new therapeutic possibilities. Moreover, well-established drugs, such as angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), or beta-blockers, show that their mechanism of action may be the result of parallel pathways other than the ones initially established. A detailed analysis of the RAS can be carried out in part through the study of the enzymes, named angiotensinases, involved in its cascade, whose activity is a reflection of the functionality of their peptide substrates. The study of these enzymes offers the possibility of controlling the effects of angiotensins through various pharmacological manipulations. For example, angiotensinase inhibitors or activators are being used or have been proposed as antihypertensive agents. They have also been suggested as analgesic and antidepressant drugs or targets for drug development against different pathologies such as Alzheimer's disease, epilepsy or ischemia. On the other hand, the analysis of brain asymmetry has revealed surprising results about the laterality of central and peripheral components of the RAS. Such studies indicate that the neurovisceral integration, already proposed by Claude Bernard (1867) should also be analyzed from a bilateral perspective. In this review, the RAS and the role of various angiotensinases implicated in the cascade are revisited. Therapeutic strategies involving some components of the RAS with an unusual vision resulting from a bilateral perspective added to their study are discussed.

Objective: Smokers are characterized by a low-grade systemic inflammatory state and an oxidant-antioxidant imbalance. Few human studies were conducted on the effects of resveratrol, a natural compound with anti-inflammatory and antioxidant properties, and no trial on smokers has been performed to date. We evaluated whether resveratrol has beneficial effects on markers of inflammation and oxidative stress in smokers. Methods and Results: A randomized, double- blind, cross-over trial was performed in 50 healthy adult smokers: 25 were randomly allocated to “resveratrol-first” (30-days: 500mg resveratrol/day, 30-days wash-out, 30-days placebo) and 25 to “placebo-first” (30-days placebo, 30-days wash-out, 30-days 500mg resveratrol/day). Resveratrol significantly reduced C-reactive protein (CRP) and triglyceride concentrations, and increased Total Antioxidant Status (TAS) values. After analyzing data with general linear models to assess period and carry-over effects, the ratios of the values after resveratrol to those after placebo were respectively: 0.47 (95%CI 0.38-0.59) –CRP- and 0.71 (95%CI 0.65-0.78) –triglycerides-, while TAS increased by 74.2 μmol/L (95%CI 60.8-87.6). Uric acid, glucose, insulin, cholesterol, liver enzyme concentrations, and weight, waist circumference, and blood pressure values did not significantly change after resveratrol supplementation. Conclusions: Because resveratrol has anti-inflammatory, anti-oxidant, and hypotriglyceridemic effects, its supplementation may beneficially affect the increased cardiovascular risk of healthy smokers.