Ernst Schering Foundation symposium proceedings最新文献

The metabolome of a cancer cell is likely to show changes after responding to an anticancer drug. These changes could be used to decide whether to continue treatment or, in the context of a drug trial, to indicate whether the drug is working and perhaps its mechanism of action. (Nuclear) magnetic resonance spectroscopy (NMR/MRS) methods can offer important insights into novel anticancer agents in order to accelerate the drug development process including time-course studies on the effect of a drug on its site of action (termed pharmacodynamics), in this case the cancer. In addition, some classes of anticancer agents currently under development (e.g. antiangiogenics) are designed to be used in combination with other drugs and will not cause tumour shrinkage when used as single agents in Phase 1 clinical trials. Thus NMR/MRS may have a special role in monitoring the pharmacodynamic actions of such drugs in early-phase clinical trials. This review focuses on the use of ex vivo NMR and in vivo MRS methods for monitoring the effect of some novel anticancer drugs on the cancer metabolome. Ex vivo NMR methods are complementary to in vivo measurements, as they can provide additional information and help in the interpretation of the in vivo data.

Within the context of Lewis base catalysis N-heterocyclic carbenes represent an extremely versatile class of organocatalyst that allows for a great variety of different transformations. Starting from the early investigations on benzoin, and later Stetter reactions, the mechanistic diversity of N-heterocyclic carbenes, depending on their properties, has led to the development of several unprecedented catalytic reactions. This article will provide an overview of the versatile reactivity of N-heterocyclic carbenes.

The metabolic phenotype of tumor cells promote the proliferative state, which indicates that (a) cell transformation is associated with the activation of specific metabolic substrate channels toward nucleic acid synthesis and (b) increased expression phosphorylation, allosteric or transcriptional regulation of intermediary metabolic enzymes and their substrate availability together mediate unlimited growth. It is evident that cell transformation due to various K-ras point mutations is associated with the activation of specific metabolic substrate channels that increase glucose channeling toward nucleic acid synthesis. Therefore, phosphorylation, allosteric and transcriptional regulation of intermediary metabolic enzymes and their substrate availability together mediate cell transformation and growth. In this review, we summarize opposite changes in metabolic phenotypes induced by various cell-transforming agents, and tumor growth-inhibiting drugs or phytochemicals, or novel synthetic antileukemic drugs such as imatinib mesylate (Gleevec). Metabolic enzymes that further incite growth signaling pathways and thus promote malignant cell transformation serve as high-efficacy nongenetic novel targets for cancer therapies.

Recognition of microbial infection and initiation of immune responses are controlled by multiple mechanisms. Toll-like receptors (TLRs) are key components of the innate immune system that detect microbial infection. TLR activation helps to eliminate the invading pathogens, coordinate systemic defenses, and initiate adaptive immune responses. Despite progress elucidating the TLR signaling aspects and the physiological relevance of TLRs in microbial infections, the molecular basis of microbial recognition by TLRs is still not fully understood. In this article we focus on the availability of microbial ligands to regulate presentation to TLRs and assist in our understanding of TLR-mediated microbial recognition.

Engagement of the T cell antigen receptor (TCR) results in the activation of multiple biochemical second messenger cascades that must be integrated for the appropriate T cell response. Once the critical TCR-stimulated signaling pathway is initiated by activation of protein tyrosine kinases, a series of adapter proteins is recruited that brings tyrosine-phosphorylated phospholipase Cgamma1 into the vicinity of its substrate, phosphatidylinositol-4,5-bisphosphate, resulting in the formation of two second messengers, inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). Previous work from multiple laboratories has shown that the balance between signals downstream of IP3 versus those downstream of DAG has profound effects on the fate of the stimulated T cells. In this report we summarize our recent data indicating that one key determinant of this balance of signals is the activity of members of the diacylglycerol kinase family, enzymes that convert DAG into phosphatidic acid.

Fragment-based drug discovery (FBDD) is established as an alternative approach to high-throughput screening for generating novel small molecule drug candidates. In FBDD, relatively small libraries of low molecular weight compounds (or fragments) are screened using sensitive biophysical techniques to detect their binding to the target protein. A lower absolute affinity of binding is expected from fragments, compared to much higher molecular weight hits detected by high-throughput screening, due to their reduced size and complexity. Through the use of iterative cycles of medicinal chemistry, ideally guided by three-dimensional structural data, it is often then relatively straightforward to optimize these weak binding fragment hits into potent and selective lead compounds. As with most other lead discovery methods there are two key components of FBDD; the detection technology and the compound library. In this review I outline the two main approaches used for detecting the binding of low affinity fragments and also some of the key principles that are used to generate a fragment library. In addition, I describe an example of how FBDD has led to the generation of a drug candidate that is now being tested in clinical trials for the treatment of cancer.

The mammary gland undergoes extensive epithelial expansion and differentiation during pregnancy, leading ultimately to the development of functional milk-producing alveolar lobules. This phase of mammary gland remodeling is controlled primarily by the cooperative interplay between hormonal signals initiated by both progesterone and prolactin. Abrogation of mammary epithelial expression of receptors for either one of the hormones results in failure of alveologenesis and an absence of pregnancy-induced tertiary ductal side branches in the case of progesterone receptor-null (PRKO) mammary glands. By combining gene array approaches to identify PR- and prolactin (PRL)-dependent downstream signaling pathways and by using genetic mouse models to address the consequences of abrogation and/or misexpression of potential downstream genes, recent studies have begun to illuminate key signaling pathways that mediate the morphogenic effects of these hormones during pregnancy-induced mammary gland remodeling. Analysis of deregulated expression of PR-dependent gene transcripts in PRKO mammary glands has revealed that convergence between progesterone and prolactin signaling occurs in part through progesterone-dependent induction of mammary epithelial PRL receptors to prime the mammary epithelium to respond to PRL. Additional genes activated by PRs encode epithelial paracrine growth factor signals that regulate ductal and alveolar epithelial proliferation and survival, lineage-restricted transcription factors that control luminal and alveolar cell fate establishment and maintenance, and gap junction proteins that play a critical role in alveolar morphogenesis by establishment of epithelial cell polarity. Finally, two distinct isoforms of PRs (PR-A and PR-B) are coexpressed in the mammary gland and display extensively overlapping but partially distinct gene regulatory properties in relaying the progesterone signal.