The promise of structural genomics in the discovery of new antimicrobial agents

Structural Genomics stands out among the emerging fields of proteomics since it influences the drug discovery process at so many points. Recent developments in protein expression technologies, x-ray crystallography and NMR spectroscopy provide the essential elements for high-throughput structure determination platforms. Bioinformatics methods to interrogate the resulting data will provide comprehensive, genome-wide databases of protein structure. Genomic sequencing and methods for high-throughput expression and protein purification are furthest advanced for microbial genes and so these have been the early targets for structural genomics initiatives. The information will be invaluable in understanding gene function, designing broad-spectrum small molecule inhibitors and in better understanding drug-host interactions.     

Chemical ligands, genomics and drug discovery

The sequencing of the human genome and numerous pathogen genomes has resulted in an explosion of potential drug targets. These targets represent both an unprecedented opportunity and a technological challenge for the pharmaceutical industry. A new strategy is required to initiate small-molecule drug discovery with sets of incompletely characterized, disease-associated proteins. One such strategy is the early application of combinatorial chemistry and other technologies to the discovery of bioactive small-molecule ligands that act on candidate drug targets. Therapeutically active ligands serve to concurrently validate a target and provide lead structures for downstream drug development, thereby accelerating the drug discovery process.     

Chemical genomics as an emerging paradigm for postgenomic drug discovery

Chemical genomics approaches are evolving to overcome key problems limiting the efficiency of drug discovery in the postgenomic era. Many of these stem from the low success rates in finding drugs for novel genomics targets whose biochemical properties and therapeutic relevance is poorly understood. The fundamental objective of chemical genomics is to find and optimize chemical compounds that can be used to directly test the therapeutic relevance of new targets revealed through genome sequencing. An integrated approach to chemical genomics encompasses a diverse set of tools including quantitative affinity-based screens, computer-directed combinatorial chemistry, and structure-based drug design. The approach is most effectively applied across targets classes whose members are structurally related, and where some members are known to have bona fide therapeutic relevance.     

Harnessing the cyclization strategy for new drug discovery

The design of new ligands with high affinity and specificity against the targets of interest has been a central focus in drug discovery. As one of the most commonly used methods in drug discovery, the cyclization represents a feasible strategy to identify new lead compounds by increasing structural novelty, scaffold diversity and complexity. Such strategy could also be potentially used for the follow-on drug discovery without patent infringement. In recent years, the cyclization strategy has witnessed great success in the discovery of new lead compounds against different targets for treating various diseases. Herein, we first briefly summarize the use of the cyclization strategy in the discovery of new small-molecule lead compounds, including the proteolysis targeting chimeras (PROTAC) molecules. Particularly, we focus on four main strategies including fused ring cyclization, chain cyclization, spirocyclization and macrocyclization and highlight the use of the cyclization strategy in lead generation. Finally, the challenges including the synthetic intractability, relatively poor pharmacokinetics (PK) profiles and the absence of the structural information for rational structure-based cyclization are also briefly discussed. We hope this review, not exhaustive, could provide a timely overview on the cyclization strategy for the discovery of new lead compounds.     

Recent progress in the discovery of Akt inhibitors as anticancer agents

Akt, also referred to as protein kinase B (PKB) or Related to A and C (RAC), is one of the major direct downstream targets of phosphoinositide 3-kinase (PI3K). As it plays a central role in promoting cancer cell proliferation and survival through a growing list of key substrates, intense efforts are underway to find inhibitors of Akt for the treatment of cancer. Discovery of potent and novel inhibitors of Akt has been facilitated greatly by the availability of the X-ray structure of the active form of Akt and by its structural similarity with other serine/threonine kinases. In this review, new Akt inhibitors for the treatment of cancer are comprehensively reviewed, with emphasis on small molecule inhibitors that bind to the ATP-binding site, allosteric sites and the PH domains. Inhibitors of pseudosubstrates and antisense oligonucleotides, as well as Akt inhibitors with unknown mechanism of actions, are also reviewed. Results of clinical trials of several Akt drug candidates are briefly discussed. A brief summary of Akt structure and regulation and the evidences supporting Akt as a cancer target is provided as well. The patent literature is surveyed through July 2007.     

A new drug-delivery-system of anticancer agents: activated carbon particles adsorbing anticancer agents

A new drug delivery system comprizing activated carbon particles adsorbing anticancer agents has been developed in order to enhance anticancer efficacy on local lesions and to reduce systemic toxicity. The system is designed to release the adsorbed anticancer agent slowly at a designated concentration level at the local site, and to allow the agent to remain for a long time at the local site, with affinity for the lymphatic system and the surface of cancer cells. Through this process, anticancer efficacy is enhanced at the local lesion and systemic toxicity decreases. Because the size of the particles influences the distribution of the agent, size is selected according to both targeted organs, i.e. lymphatic metastases, carcinomatous peritonitis, and administration methods, i.e. intramural, intracavitary, intrabronchial, or intratumoral administration.     

新药研发风险的应对策略

目的探讨新药研发风险的应对策略。方法运用风险管理理论分析新药研发风险类型和特点,提出相应的对策。结果通过分析,得出政策风险、法律风险等八大风险的应对策略。结论通过合理的风险应对策略可以减少或化解各种新药研发风险。     

Microbial genomics and novel antibiotic discovery: new technology to search for new drugs

The process of prokaryotic drug discovery has been a model of success for over fifty years, yet the number of exploited bacterial targets is a mere fraction, less than 0.1% of the potential targets (based on total number of bacterial genes identified by gene sequence projects). To better understand the potential for drug intervention, multiple paradigms have been established in the pharmaceutical industry, all with some semblance of commonality and uniqueness to provide proprietary positioning, yet no company has been successful to date in taking a genomics approach to the finish line of having a genomics-based drug on the market. Within this overview, we provide a strategic overview of a sample process for the identification, validation and exploitation of novel antibacterial targets ascertained through a bioinformatics-based genomics drug discovery program.     

Podophyllotoxin derivatives: current synthetic approaches for new anticancer agents

Podophyllotoxin is an antimitotic natural product. Its inhibitory activity on cell growth led to the development of the clinically valuable anticancer agents, etoposide, teniposide and the water-soluble prodrug, etoposide phosphate. The cytotoxic mechanism of these drugs is the inhibition of topoisomerase II, unlike the lead compound which inhibits mitosis. Through extensive structure-activity relationship studies, several potential drug candidates were synthesized such as GL-331, TOP 53, NK611, and azatoxin. Recently, more complex and diverse analogues have been synthesized either to get more potent compounds or to overcome drug resistance. At the same time, a number of prodrug approaches have been tried to enhance the tumor selectivity or to increase the aqueous solubility. The prodrugs can release cytotoxic etoposide through the actions of hydrolysis, enzymes or catalytic antibodies. More sophisticated prodrug strategies have been applied in etoposide and these produced some interesting results. In this review, the current research trends in the design of new derivatives will be covered with a brief introduction of podophyllotoxin and related analogues.     

Inhibitors of histone deacetylase as new anticancer agents

Inhibitors of histone deacetylase (HDAC) are an emerging class of anticancer agents. They induce hyperacetylation in chromatin usually resulting in activation of certain genes. They induce terminal cell differentiation and/or apoptosis in cancer cells. Histone deacetylase activity is recruited by co-repressor proteins to certain regions of the chromatin and aberrant histone acetylation caused by that recruitment is responsible for the pathogenesis of certain cancers on a molecular level. Inhibitors of HDAC have been identified in natural sources and also synthetic inhibitors are available. The best studied inhibitor is trichostatin A, a hydroxamic acid that exerts its activity by complexation of a zinc ion that is supposed to mediate the acetamide cleavage at the catalytic site. There are several synthetic hydroxamic acids that bear resemblance to trichostatin. Another class of potent inhibitors are naturally occurring and synthetic cyclotetrapeptides that all contain an unusual amino acid with an epoxyketone, ketone or hydroxamic acid function in the side chain. Phenylacetate, phenylbutyrate, butyrate and similar short chain fatty acids are also weak inhibitors. Further inhibitors from natural sources are the epoxide depudecin and depsipeptide FR 901228. The benzamide MS-275 belongs to a new class of synthetic HDAC inhibitors and displays oral activity in animal models. First clinical studies have shown that histone hyperacetylation can be achieved safely in humans and that treatment of cancer is possible. Thus, inhibitors of HDAC are one of the most promising class of new anticancer agents. New screening assays are useful tools that will facilitate identification of further inhibitors.     

ROS-activated anticancer prodrugs: a new strategy for tumor-specific damage

Targeting tumor cells is an important strategy to improve the selectivity of cancer therapies. With the advanced studies in cancer biology, we know that cancer cells are usually under increased oxidative stress. The high level of reactive oxygen species in cancer cells has been exploited for developing novel therapeutic strategies to preferentially kill cancer cells. Our group, amongst others, have used boronic acids/esters as triggers for developing ROS-activated anticancer prodrugs that target cancer cells. The selectivity was achieved by combining a specific reaction between boronates and H2O2, with the efficient masking of drug toxicity in the prodrug via boronates. Prodrugs activated via ferrocene-mediated oxidation have also been developed to improve the selectivity of anticancer drugs. We describe how the strategies of ROS-activation can be used for further development of new ROS-targeting prodrugs, eventually leading to novel approaches and/or combined technology for more efficient and selective treatment of cancers.     

Bacterial genomics as a potential tool for discovering new antimicrobial agents

The past 30 years have witnessed the emergence of new infectious diseases as well as the re-emergence of those thought to be defeated or under control. It is likely that this threat will continue and that infectious micro-organisms will be found to be responsible for numerous diseases whose etiology had been previously unknown. Compounding this threat is the rapid evolution of drug resistance by micro-organisms that is rendering many existing antimicrobial agents obsolete. Thus, there is an urgent need for the development of new classes of antimicrobial agents and the identification of new drug targets. Over the past decade, advances in high-throughput automated DNA sequencing have delivered a wealth of genetic information in the form of whole genome sequences of microbial pathogens. Coupled with this advancement has been the development of new genetic tools and computational advances capable of selecting genes of particular interest as well as testing for the effects of candidate drugs. While no new drugs have yet been developed, further study into the application and limitations of these new approaches to the identification of novel targets will aid in overcoming the current problem of antimicrobial drug resistance.     

Novel genetic techniques and approaches in the microbial genomics era: identification and/or validation of targets for the discovery of new antibacterial agents

The availability of microbial genome sequences has ushered in the genomics era and has led to numerous technical advancements over the past decade. These advances have been both in the bioinformatics field that has integrated computer-based approaches with biology and in research methods in the laboratory. The advances have assisted scientists in their study of bacterial gene complements and the roles of their gene products in the bacterial life cycle. Assignment of genes as essential to the bacterial cell nominated them as potential targets for antibacterial drugs and spurred attempts to exploit this information and convert it into drugs. At present, these efforts have met with minimal success. There are several possible reasons for these disappointing results including choice of targets and screen designs, compound libraries chosen for screens, and decreased commitment to antibacterial drug discovery by many large pharmaceutical companies. Structure-based approaches could become very effective in the future as methodologies continue to improve.     

Integrated bacterial genomics for the discovery of novel antimicrobials

Sequencing of bacterial genomes has been progressing with breathtaking speed. Currently, the genomes of 23 bacterial species are sequenced, with approximately 40 more sequencing projects in progress. Industrial research is now facing the challenge of translating this information efficiently into drug discovery. This review will summarize the impact of bacterial genomics, bioinformatics and second-generation genomic technologies on target identification, assay development, lead optimization and compound characterization.     

Current targets for anticancer drug discovery

The call for the discovery of less toxic, more selective, and more effective agents to treat cancer has become more urgent. Inhibition of angiogenesis continues to be one of the main streams in the current cancer drug discovery activity. Insights into tumor angiogenesis biology have led to the identification of a number of molecules, which are important for the progression of these processes. Of particular interest is a group of growth factors including fibroblast growth factor, platelet-derived growth factor, and vascular endothelial growth factor. These growth factors and their corresponding receptor tyrosine kinases have become important targets for inhibition of the proliferation of endothelial cells, the main component of blood vessels. The validated targets for inhibition of angiogenesis also include a family of matrix metalloproteinases and cell adhesion molecules. In the closely related area, protein kinases have emerged as one of the most important targets for drug discovery. Besides growth factor receptor tyrosine kinases, numerous other protein kinases implicated in malignancies have been identified including non-receptor kinases such as Bcl-Abl and Src kinases. In addition, the cell cycle regulators (cyclin-dependent kinases, p21 gene) and apoptosis modulators (Bcl-2 oncoprotein, p53 tumor suppressor gene, survivin protein, etc) have also attracted renewed interest as potential targets for anticancer drug discovery. Other molecular targets include protein farnesyltransferase (FTase), histone deacetylase (HDAC), and telomerase, which have essential roles in cellular signal transduction pathways (FTase, HDAC) and cell life-span (telomerase). This review presents a comprehensive summary and discussion on the most important targets currently attracting a great deal of interest in contemporary anticancer drug design and discovery. Recent advances complementing these targets are also highlighted.     

Synthesis of some new bis-thiazoles as possible anticancer agents

Several new 5-(2,3-dihydrothiazol-2-yledinyl)rhodanines 3a-c and 5-(4-oxothiazolidinon-2-ylidenyl)rhodanine 4 were synthesized through the reaction of 5-thiocarbamoyl rhodanines 2 with phenacyl bromides or chloroacetic acid, respectively. The synthesis of the arylidene derivatives 5a-c were also described. The 5-(4-amino-5-cyano-2,3-dihydrothiazol-2-yledinyl)rhodanines 10a, b were obtained through reaction of rhodanines 1a, b with thiazolium salt 9. All the prepared compounds were screened for their anticancer activity using the NCI in vitro anticancer screening program. Three compounds showed promising anticancer activity against particular human cell lines used in the assay.