Current Medicinal Chemistry - Volume 17, Issue 16, 2010

Oncogenic B-Raf has been identified in a variety of cancers with high incidence, especially in malignant melanoma and thyroid cancer. Most B-Raf mutations elicit elevated kinase activity and the constitutive activation of Ras/Raf/MEK/ERK pathway, which induces proliferation and promotes malignant transformation. Therefore, B-Raf inhibitors, targeting B-Raf or mutated B-Raf, have received increasing momentum in oncology drug discovery arena. This review focuses on the diverse small-molecule inhibitors of B-Raf kinase recently reported in the literature, including those currently in clinical and preclinical phase. They are described as two categories, type I or type II kinase inhibitors, based on their different mechanism of action with active or inactive conformations of the B-Raf kinase derived from the available crystal structures or molecular docking analysis. A particular emphasis is placed on their binding modes and the structure-activity relationship (SAR) of each chemical structure class.

A large number of herbal remedies (e.g. garlic, mistletoe, Essiac, Lingzhi, and astragalus) are used by cancer patients for treating the cancer and/or reducing the toxicities of chemotherapeutic drugs. Some herbal medicines have shown potentially beneficial effects on cancer progression and may ameliorate chemotherapy-induced toxicities. However, there is no or weak scientific basis for the clinical use of these herbal medicines in cancer management and almost none of these plant medicines have been tested in rigorous clinical trials. There are increased reports on the interaction of herbal medicines and anticancer drugs that is becoming a safety concern. For example, a clinical study in cancer patients reported that treatment of St John's wort at 900 mg/day orally for 18 days decreased the plasma levels of the active metabolite of irinotecan, SN-38, by 42%. In healthy subjects, 2 weeks of treatment with St John's wort at 900 mg/day significantly decreased the systemic exposure of imatinib by 32%. In women with advanced breast cancer, coadministration of garlic supplement reduced the clearance of docetaxol by 23.1-35.1%, although the difference did not achieve statistical significance. Most anticancer drugs undergo Phase I and/or II metabolism and are substrates of P-glycoprotein, breast cancer resistance protein, multidrug resistance associated proteins, and/or other transporters. Induction and inhibition of these enzymes and transporters are considered as important mechanisms for herb-anticancer drug interactions. Further studies are warranted to investigate potentially harmful herbal interactions with anticancer drugs in patients.

Fabry disease (FD) is an X-linked glycosphingolipid storage disorder caused by deficient activity of the lysosomal enzyme α -galactosidase A. This leads to a progressive accumulation of globotriaosylceramide (Gb3) in the lysosomes of different cells and tissues, causing principally ventricular hypertrophy, renal failure and cerebrovascular accidents, reducing lifespan both in hemizygous males and heterozygous females. Residual enzyme activity might lead to slow progression of the disease and result in the so-called cardiac or renal variants with delayed presentation. Two different forms of α-galactosidase A enzyme replacement therapies (ERT) are available for the treatment of FD, one genetically engineered in human cell line (agalsidase alfa, Replagal®, Shire) and the other produced in a Chinese hamster ovary cell line (agalsidase beta, Fabrazyme®, Genzyme). Although both proteins are structurally and functionally very similar, with the same amino acid sequence as the native human enzyme, they differ in the pattern of glycosilation of the protein depending on the originating cell line. Studies with both preparations have described a reduction in plasma, urinary sediment and tissue levels of Gb3, a decrease in the frequency of pain crisis and a reduction in left ventricular mass and improvement or stabilization of renal function. Studies have generally shown the greatest benefit when treatment is started at an early stage of the disease before extensive fibrosis or other irreversible tissue damage takes place. However, more data are needed to document long-term treatment outcomes. The aim of the present review is to provide an updated overview of the two different forms of ERT for FD, their clinical effects in cardiac manifestations and their possible differences in terms of efficacy, side effects and safety profiles.

Recent evidence suggests that vascular inflammation plays important role in the pathogenesis and the clinical evolution of atherosclerosis. Several circulating inflammatory biomarkers such as acute phase proteins, adhesion molecules and pro-inflammatory cytokines along with biomarkers, proposed the last few years, have clarified the role of inflammation in atherosclerosis. In particular a number of studies have focused on the positive predictive role of C-reactive protein in populations without prior cardiovascular disease. As regards to fibrinogen studies have shown a positive role in predicting cardiovascular events. However, the potential prognostic role of adhesion molecules and cytokines for cardiovascular events is unclear. Thus, further studies are required to evaluate the predictive role of such molecules, as well as others under investigation in states of atherosclerosis.

The poisoning with organophosphorus compounds represents a life threatening danger especially in the time of terroristic menace. No universal antidote has been developed yet and other therapeutic approaches not related to reactivation of acetylcholinesterase are being investigated. This review describes the main features of the cholinergic system, cholinergic receptors, cholinesterases and their inhibitors. It also focuses on the organophosphorus nerve agents, their properties, effects and a large part describes various possibilities in treatments, mainly traditional oxime therapies based on reactivation of AChE. Furthermore, non-cholinesterase coupled antidotal effects of the oximes are thoroughly discussed. These antidotal effects principally include oxime interactions with muscarinic and nicotinic receptors.

It takes about 10 to 15 years and roughly 800 mln $ to bring a new drug to the market. Only 10% of drug molecules entering clinical trials succeed and only 3 out of 10 drugs generate enough profit to pay back for the investment. Drug targets may be searched by hypothesis driven modeling of molecular networks within and between cells by systems biology. However, there is the potential to simplify the search for new drugs and drug targets by an initial top-down cytomics phase. The cytomics approach i) requires no detailed a-priori knowledge on mechanisms of drug activity or complex diseases, ii) is hypothesis driven for the investigated parameters (genome, transcriptome, proteome, metabolome a.o.) and iii) is hypothesis-free for data analysis. Moreover it iv) carries the potential to uncover unknown molecular interrelations as a prerequisite for later new hypothesis driven modeling and research strategies. A set of discriminatory parameter patterns (molecular hotspots) describing the cellular model (mechanism of drug action) can be identified by differential molecular cell phenotyping. Hereby, the immediate modeling of existing complexities by bottom-up oriented systems biology is avoided. The review focuses on the fast technological developments of molecular single cell analysis in recent years. They comprise a multitude of sensitive new molecular markers as well as various new image and flow cytometric high-content screening methods as facilitators of the cytomics concept. New bioinformatic tools enable the extraction of relevant molecular hotspots in description of cellular models, being required for the subsequent molecular reverse engineering phase by systems biology.