Design, synthesis and evaluation of new 6-substituted-5-benzyloxy-4-oxo-4H-pyran-2-carboxamides as potential Src inhibitors

Src family kinases (SFKs) are nonreceptor tyrosine kinases that are reported to be critical for cancer progression. Inhibiting the catalytic activity of these proteins has become one of the major therapeutic concepts in contemporary drug discovery. We report here the design and the synthesis of novel 6-substituted-5-benzyloxy-4-oxo-4H-pyran-2-carboxamides as potential inhibitors of Src kinase. The synthesis of these derivatives and the preliminary results of biological activity will be discussed.     

Modern approaches to drug discovery and design: setting the scene

The raison d'ítre for the drug discovery and development process is to provide safe and effective treatments for diseases. Bringing a new drug to market, however, is a time-consuming and expensive process and it remains an imperative for drug companies that they identify ways in which they can accelerate the identification of potential targets and their screening and development in order to maintain a competitive edge. Successful drug discovery efforts include biochemical, biophysical, genetic and immunological approaches, targeting such processes as signal transduction, cell cycle control, apoptosis, gene regulation and metastasis. As the number of these biological targets increases, reliance on bioinformatics and chemoinformatics to improve decision making, by identifying characteristics of successful drugs and sharing knowledge gained within the scientific community, has become a burgeoning area in the post-genomic era of drug discovery.     

Design,synthesis and evaluation of new 6-substituted-5-benzyloxy-4-oxo-4H-pyran-2-carboxamides as potential Src inhibitors

Src family kinases (SFKs) are nonreceptor tyrosine kinases that are reported to be critical for cancer progression. Inhibiting the catalytic activity of these proteins has become one of the major therapeutic concepts in contemporary drug discovery. We report here the design and the synthesis of novel 6-substituted-5-benzyloxy-4-oxo-4H-pyran-2-carboxamides as potential inhibitors of Src kinase. The synthesis of these derivatives and the preliminary results of biological activity will be discussed.     

Proteomics in the post-genome age.

The genome sequencing effort has helped spawn the burgeoning field of proteomics. This review article examines state-of-the-art proteomics methods that are helping change the discovery paradigm in a variety of biological disciplines and, in particular, protein biochemistry. The review discusses both classical and novel methods to perform high-throughput qualitative and quantitative "global" as well as targeted proteome analysis of complex biological systems. From a drug discovery standpoint, the synergy between genomics and proteomics will help elucidate disease mechanisms, identify novel drug targets, and identify surrogate biomarkers that could be used to conduct clinical trials.     

Chemogenomics: drug discovery's panacea?

Chemogenomics aims towards the systematic identification of small molecules that interact with the products of the genome and modulate their biological function. This Opinion article summarizes the different knowledge-based chemogenomics strategies that are followed and outlines the challenges and opportunities that will impact drug discovery. Chemogenomics aims towards the systematic identification of small molecules that interact with the products of the genome and modulate their biological function. While historically the approach is based on efforts that systematically explore target gene families like kinases, today additional knowledge-based systematization principles are followed within early drug discovery projects which aim to biologically validate the targets and to identify starting points for chemical lead optimization. While the expectations of chemogenomics are very high, the reality of drug discovery is quite sobering with very high project attrition rates. This article summarizes the different knowledge-based chemogenomics strategies that are followed and outlines the challenges and potential opportunities that will impact drug discovery.     

药物靶点的选择和验证

药物靶点的选择和验证是药物开发研究中一个重要的环节.随着现代分子生物学技术的发展和人类基因组计划的完成,出现了大量可供治疗干预的新型分子靶点,对这些新型分子靶点进行验证成为药物开发科学家所面临的重要任务.为此,就药物靶点及其选择、验证所需的分子技术基础作一简要综述.     

Computer-aided drug discovery and development (CADDD): in silico-chemico-biological approach

It is generally recognized that drug discovery and development are very time and resources consuming processes. There is an ever growing effort to apply computational power to the combined chemical and biological space in order to streamline drug discovery, design, development and optimization. In biomedical arena, computer-aided or in silico design is being utilized to expedite and facilitate hit identification, hit-to-lead selection, optimize the absorption, distribution, metabolism, excretion and toxicity profile and avoid safety issues. Commonly used computational approaches include ligand-based drug design (pharmacophore, a 3D spatial arrangement of chemical features essential for biological activity), structure-based drug design (drug-target docking), and quantitative structure-activity and quantitative structure-property relationships. Regulatory agencies as well as pharmaceutical industry are actively involved in development of computational tools that will improve effectiveness and efficiency of drug discovery and development process, decrease use of animals, and increase predictability. It is expected that the power of CADDD will grow as the technology continues to evolve.     

Applications of cell-based phage display panning to proteomic analysis

In the post-genomic era, proteomics together with genomic tools have led to powerful new strategies in basic and clinical research. These combined “omics” technologies are being integrated into the drug target discovery process. Unlike the genome, the proteome is a highly dynamic entity that requires techniques capable of analyzing on selected populations of proteins in specific biological conditions that reflect the proteins’ functional characteristics. Antibodies have become one of the most important reagents for the analysis of selected populations of proteins, and the application of phage-display antibody libraries to high-throughput antibody generation against large numbers of various antigens provides a tool for proteome-wide protein expression analysis. In this review, we will discuss the utility of phage-display antibodies in proteomics applications, specifically for the discovery of novel disease markers and therapeutic targets.     

Process biology: integrated genomics and bioinformatics tools for improved target assessment

The availability of the human genome sequence has greatly increased the number of potential drug targets in recent years. As a result, the way targets are assessed has become crucial to the success of the drug discovery process. Unfortunately, the traditional methods relied on by the pharmaceutical industry to identify and validate targets are too slow and labor-intensive to be useful in the current environment. One solution to this dilemma is to adopt a new paradigm, which we call Process Biology. Process Biology integrates genomics and bioinformatics tools into automated, optimized modules that can be applied readily to a wide range of biological questions. By using organizational principles not usually applied to biological experiments, Process Biology can significantly impact target assessment and assist in decision-making throughout the drug discovery process.     

靶向肿瘤血管生成的天然产物研究进展

血管生成在肿瘤的发生发展过程中起着非常重要的作用.促血管生成因子及其受体可以通过调节血管生成促进肿瘤发生发展.因此,发现和开发靶向血管生成因子药物已经成为治疗肿瘤的重要策略.近年来,天然产物因其结构多样、毒副作用低及作用机制独特等优势已然成为开发抗肿瘤药物的主要来源.本文归纳阐述了近年来靶向血管生成因子具有抗肿瘤活性的...     

Development of new RNAi therapeutics

RNAi-mediated gene inactivation has become a cornerstone of the present day gene function studies that are the foundation of mechanism and target based drug discovery and development, which could potentially shorten the otherwise long process of drug development. In particular, the coming of age of "RNAi drug" could provide new promising therapeutics bypassing traditional approaches. However, there are technological hurdles need to overcome and the biological limitations need to consider for achieving effective therapeutics. Major hurdles include the intrinsic poor pharmacokinetic property of siRNA and major biological restrictions include off-target effects, interferon response and the interference with endogenous miRNA. Recent innovations in nucleic acid chemistry, formulations and delivery methods have gradually rendered it possible to develop effective RNAi-based therapeutics. Careful design based on the newest RNAi/miRNA biology can also help to minimize the potential tissue toxicity. If successful with systemic application, RNAi drug will no doubt revolutionize the whole drug development process. This review attempts to describe the progress in this area, including applications in preclinical models and recent favorable experience in a number of human trials of local diseases, along with the discussion on the potential limitations of RNAi therapeutics.     

Towards a molecular characterisation of pathological pathways

The dominant conceptual reductionism in drug discovery has resulted in many promising drug candidates to fail during the last clinical phases, mainly due to a lack of knowledge about the patho-physiological pathways they are acting on. Consequently, to increase the revenues of the drug discovery process, we need to improve our understanding of the molecular mechanisms underlying complex cellular processes and consider each potential drug target in its full biological context. Here, we review several strategies that combine computational and experimental techniques, and suggest a systems pathology approach that will ultimately lead to a better comprehension of the molecular bases of disease.     

Advances and applications of binding affinity prediction methods in drug discovery

Nowadays, the improvement of R&D productivity is the primary commitment in pharmaceutical research, both in big pharma and smaller biotech companies. To reduce costs, to speed up the discovery process and to increase the chance of success, advanced methods of rational drug design are very helpful, as demonstrated by several successful applications. Among these, computational methods able to predict the binding affinity of small molecules to specific biological targets are of special interest because they can accelerate the discovery of new hit compounds. Here we provide an overview of the most widely used methods in the field of binding affinity prediction, as well as of our own work in developing BEAR, an innovative methodology specifically devised to overtake some limitations in existing approaches. The BEAR method was successfully validated against different biological targets, and proved its efficacy in retrieving active compounds from virtual screening campaigns. The results obtained so far indicate that BEAR may become a leading tool in the drug discovery pipeline. We primarily discuss advantages and drawbacks of each technique and show relevant examples and applications in drug discovery.     

Drug discovery considerations in the development of covalent inhibitors

In recent years, the number of drug candidates with a covalent mechanism of action progressing through clinical trials or being approved by the FDA has increased significantly. And as interest in covalent inhibitors has increased, the technical challenges for characterizing and optimizing these inhibitors have become evident. A number of new tools have been developed to aid this process, but these have not gained wide-spread use. This review will highlight a number of methods and tools useful for prosecuting covalent inhibitor drug discovery programs.     

DNA微阵列技术在阿尔茨海默病及其防治药物研究中的应用

在生物技术飞速发展的今天,DNA微阵列已成为功能基因组时代大规模、高通量乃至全基因组表达和功能研究的有力工具。阿尔茨海默病,因其发病机制复杂,迄今尚无定论,因此在临床上也缺乏有效的防治药物。简要综述DNA微阵列技术应用于阿尔茨海默病发病机制、早期诊断及防治药物等方面的研究进展。     

Significance of the zebrafish model in the discovery of bioactive molecules from nature

Natural products have immense therapeutic potential not only due to their structural variation and complexity but also due to their range of biological activities. Research based on natural products has led to the discovery of molecules with biomedical and pharmaceutical applications in different therapeutic areas like cancer, inflammation responses, diabetes, and infectious diseases. There are still several challenges to be overcome in natural product drug discovery research programs and the challenge of high throughput screening of natural substances is one of them. Bioactivity screening is an integral part of the drug discovery process and several in vitro and in vivo biological models are now available for this purpose. Among other well-reported biological models, the zebrafish (Danio rerio) is emerging as an important in vivo model for preclinical studies of synthetic molecules in different therapeutic areas. Zebrafish embryos have a short reproductive cycle, show ease of maintenance at high densities in the laboratory and administration of drugs is a straightforward procedure. The embryos are optically transparent, allowing for the visualization of drug effects on internal organs during the embryogenesis process. In this review, we illustrate the importance of using zebrafish as an important biological model in the discovery of bioactive drugs from natural sources.     

Phenocopy--a strategy to qualify chemical compounds during hit-to-lead and/or lead optimization

A phenocopy is defined as an environmentally induced phenotype of one individual which is identical to the genotype-determined phenotype of another individual. The phenocopy phenomenon has been translated to the drug discovery process as phenotypes produced by the treatment of biological systems with new chemical entities (NCE) may resemble environmentally induced phenotypic modifications. Various new chemical entities exerting inhibition of the kinase activity of Transforming Growth Factor β Receptor I (TGF-βR1) were qualified by high-throughput RNA expression profiling. This chemical genomics approach resulted in a precise time-dependent insight to the TGF-β biology and allowed furthermore a comprehensive analysis of each NCE's off-target effects. The evaluation of off-target effects by the phenocopy approach allows a more accurate and integrated view on optimized compounds, supplementing classical biological evaluation parameters such as potency and selectivity. It has therefore the potential to become a novel method for ranking compounds during various drug discovery phases.     

A study on the correlation of G-protein-coupled receptor types with amino acid composition

G-protein-coupled receptors have become a target in utilizing bioinformatics and genomics technology to facilitate drug discovery for psychiatric diseases. In this study the covariant-discriminant algorithm [Chou and Elrod (1999) Protein Eng., 12, 107-118] has been used to analyze the correlation between the types of G-protein-coupled receptors and the amino acid composition. It has been found that different types of G-protein-coupled receptors are quite closely correlated with the amino acid composition, implying that the types of G-protein-coupled receptors are predictable to a considerably accurate extent if a good training data set can be established for that purpose. The method derived here can be also used to do preliminary classification of orphan G-protein-coupled receptors. This will significantly expedite the process of identifying proper G-protein-coupled receptors for drug discovery.     

以生物合成为基础的代谢工程和组合生物合成

代谢工程和组合生物合成在筛选和发展新型药物方面日益成为生物、化学和医药界关注的重点。基于聚酮和聚肽类天然产物的独特化学结构和良好生物活性,研究它们的生物合成机制,将为合理化遗传修饰生物合成途径获得结构类似物提供遗传和生物化学的基础,实现利用现代生物学和化学的技术手段在微生物体内进行药物开发的目的。