Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques最新文献

Cancer is a disease of genome sequence alterations as well as epigenetic changes. Epigenetics refers in part to the mechanisms by which histones affect various DNA-based processes, such as gene regulation. Histones are proteins around which the DNA wraps itself to form chromatin--the physiologically relevant form of the human genome. Histones are modified extensively by posttranslational modifications that alter chromatin structure and serve to recruit to or exclude protein complexes from DNA. Aberrations in histone modifications occur frequently in cancer including changes in their levels and distribution at gene promoters, gene coding regions, repetitive DNA sequences, and other genomic elements. Locus-specific alterations in histone modifications may have adverse effects on expression of nearby genes but so far have not been shown to have clinical utility. Cancer cells also exhibit alterations in global levels of specific histone modifications, generating an additional layer of epigenetic heterogeneity at the cellular level in tumor tissues. Unlike locus-specific changes, the cellular epigenetic heterogeneity can be used to define previously unrecognized subsets of cancer patients with distinct clinical outcomes. In general, increased prevalence of cells with lower global levels of histone modifications is prognostic of poorer clinical outcome such as increased risk of tumor recurrence and/or decreased survival probability. Prognostic utility of histone modifications has been demonstrated independently for multiple cancers including those of prostate, lung, kidney, breast, ovary, and pancreas, suggesting a fundamental association between global histone modification levels and tumor aggressiveness, regardless of cancer tissue of origin. Cellular levels of histone modifications may also predict response to certain chemotherapeutic agents, serving as predictive biomarkers that could inform clinical decisions on choice and course of therapy. The challenge before us is to understand how global levels of histone modifications are established and maintained and what their mechanistic links are to the cancer clinical behavior.

The successful establishment and stable maintenance of cell identity are critical for organismal development and tissue homeostasis. Cell identity is provided by epigenetic mechanisms that facilitate a selective readout of the genome. Operating at the level of chromatin, they establish defined gene expression programs during cell differentiation. Among the epigenetic modifications in mammalian chromatin, the 5'-methylation of cytosine in CpG dinucleotides is unique in that it affects the DNA rather than histones and the biochemistry of the DNA methylating enzymes offers a mechanistic explanation for stable inheritance. Yet, DNA methylation states appear to be more dynamic and their maintenance more complex than existing models predict. Also, methylation patterns are by far not always faithfully inherited, as best exemplified by human cancers. Often, these show widespread hypo- or hypermethylation across their genomes, reflecting an underlying epigenetic instability that may have contributed to carcinogenesis. The phenotype of unstable methylation in cancer illustrates the importance of quality control in the DNA methylation system and implies the existence of proof-reading mechanisms that enforce fidelity to DNA methylation in healthy tissue. Fidelity seems particularly important in islands of unmethylated CpG-rich sequences where an accurate maintenance of un- or differentially methylated states is critical for stable expression of nearby genes. Methylation proof-reading in such sequences requires a system capable of recognition and active demethylation of erroneously methylated CpGs. Active demethylation of 5-methylcytosine has been known to occur for long, but the underlying mechanisms have remained enigmatic and controversial. However, recent progress in this direction substantiates a role of DNA repair in such processes. This review will address general aspects of cytosine methylation stability in mammalian DNA and explore a putative role of DNA repair in methylation control.

Recent advances in somatic cell reprogramming and directed differentiation make it possible to generate patient-specific pluripotent cells and further derive functional tissue-specific cells for biomedical research and future therapies. Chemical compounds targeting enzymes or signaling proteins are powerful tools to regulate and reveal complex cellular processes and have been identified and applied to controlling cell fate and function, including stem cell maintenance, differentiation, and reprogramming. Not only are small molecules useful in generating desired cell types in vitro for various applications, but also such small molecules could be further developed as conventional therapeutics to target patient's own cells residing in different tissues/organs for treating degenerative diseases, injuries, and cancer. Here, we will review recent studies of small molecules in controlling cell fate.

Mental retardation (MR), which affects 1-3% of the total population, refers to a pathological condition whereby the affected individuals suffer from cognitive impairment, which is diagnosed by a low intelligence quotient (IQ) (< 70). Over the years, human genetic studies identified a plethora of candidate genes causing MR, but mechanisms by which these candidates regulate cognitive function remain poorly understood. While the functions of MR genes range from cell signaling and gene expression to synaptic plasticity, there is growing evidence supporting a critical role for epigenetic and chromatin regulatory proteins in MR. Excitingly, recent molecular and genetic studies suggest the possibility of improving cognitive functions via modulation of epigenetic regulators, highlighting a potentially new avenue for therapeutic intervention. In this review, we discuss recent studies on epigenetic regulation in MR and explore the concept of epigenetic therapy for MR.

Epothilones (Epo's) A and B are naturally occurring microtubule-stabilizers, which inhibit the growth of human cancer cells in vitro at low nM or sub-nM concentrations. In contrast to taxol (paclitaxel, Taxol) epothilones are also active against different types of multidrug-resistant cancer cell lines in vitro and against multidrug-resistant tumors in vivo. Their attractive preclinical profile has made epothilones important lead structures in the search for improved cytotoxic anticancer drugs and Epo B (EPO906, patupilone) is currently undergoing Phase III clinical trials. Numerous synthetic and semisynthetic analogs have been prepared since the absolute stereochemistry of epothilones was first disclosed in mid-1996 and their in vitro biological activity has been determined. Apart from generating a wealth of SAR information, these efforts have led to the identification of at least six compounds (in addition to Epo B), which are currently at various stages of clinical evaluation in humans. The most advanced of these compounds, Epo B lactam BMS-247550 (ixabepilone), has recently obtained FDA approval for the treatment of metastatic and advanced breast cancer. This chapter will first provide a summary of the basic features of the biological profile of Epo B in vitro and in vivo. This will be followed by a review of the processes that have been developed for the fermentative production of Epo B. The main part of the chapter will focus on the most relevant aspects of the epothilone SAR with regard to effects on tubulin polymerization, in vitro antiproliferative activity, and in vivo antitumor activity. Particular emphasis will be placed on work conducted in the authors' own laboratories, but data from other groups will also be included. In a final section, the current status of those epothilone analogs undergoing clinical development will be briefly discussed.

An overview is given on current efforts in drug development based on plant-derived natural products. Emphasis is on projects which have advanced to clinical development. Therapeutic areas covered include cancer, viral infections including HIV, malaria, inflammatory diseases, nociception and vaccine adjuvants, metabolic disorders, and neurodegenerative diseases. Aspects which are specific to plant-based drug discovery and development are also addressed, such as supply issues in the commercial development, and the Convention on Biological Diversity.

Natural products (NPs) have evolved over a very long natural selection process to form optimal interactions with biological macromolecules. NPs are therefore an extremely useful source of inspiration for the design of new drugs. In the present study we report the results of a cheminformatics analysis of more than 130,000 NP structures. The physicochemical properties of NPs and their typical structural features are compared to those of bioactive molecules and average organic molecules. The relationship between the structure of NPs and the type of organism from which they have come has also been analyzed. The aim of this study was to identify those properties and structural features which are typical for NPs and discriminate this class of molecules from common synthetic molecules, with the ultimate goal being to provide a guide for the design of novel NP-like bioactive structures. Hopefully the results of this analysis help to eliminate the old myth about NPs as being 'too complex' or having 'bad properties', as well as help us to focus on these areas of NP structural space which are essential for biological activity, taking advantage of the process of natural selection over billions of years to guide us to new and as yet unexplored areas of the Chemical Structure Universe.

Today we use many drugs produced by microorganisms. However, when these drugs were discovered it was found that the yields were low and a substantial effort had to be put in to develop commercially viable processes. A key part of this endeavor was the studies of the nutritional and the engineering parameters. In this chapter, the basic principles of optimizing the nutritional and engineering aspect of the production process are described with appropriate examples. It was found that two critical components of nutritional medium, carbon and nitrogen source regulated the synthesis of the compounds of interest. Rapidly utilizable carbon source such as glucose supported the growth but led to catabolite repression and alternative carbon sources or methods of addition had to be devised. Inorganic nitrogen sources led to undesirable changes in pH of the medium. Organic nitrogen sources could influence the yields positively or negatively and had to be chosen carefully. Essential nutrients like phosphates often inhibited the synthesis and its concentration had to be maintained below the inhibitory levels. On many occasions, trace nutrients like metal ions and vitamins were found to be critical for good production. Temperature and pH were important environmental variables and their optimum values had to be determined. The media were designed and optimized initially with 'one variable at a time' approach and later with experimental design based on statistics. The latter approach is preferred because it is economical, considers interactions between medium components and allows rapid optimization of the process. The engineering aspects like aeration, agitation, medium sterilization, heat transfer, process monitoring and control, become critical as the process is scaled-up to the production size. Aeration and agitation are probably the most important variables. In many processes dissolved oxygen concentration had to be maintained above a critical value to obtain the best yields. The rheological properties of fermentation broth significantly affect the aeration and mixing efficiency. The removal of heat from the large fermentors can be difficult under certain conditions. However, new designs of impellers, availability of sensors to monitor important physiological and process variables and advent of computers have facilitated successful scale-up of fermentation processes.