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PubMedDate not supplied

Identification of genes associated with enhanced metastasis of a large cell lung carcinoma cell line.

We have compared the transcriptional profile of large cell lung tumor cell lines NIH-H460 and H460-M making use of the Affymetrix GeneChip system. H460-M is derived from NIH-H460 and displays enhanced experimental and spontaneous metastasis in nude mice. Out of the 12,600 genes investigated, 73 (0.6%) were up-regulated and 114 (0.9%) were down-regulated on the basis of the scoring criteria. We have classified the de-regulated genes according to the following categories: immune response, enzymes, modulation of transcription, signal transduction, cytoskeleton/adhesion and extracellular matrix associated proteins, cell-cycle/apoptosis, transporters and 'others'. Among the remarkable features of this system are the up-regulation of the steady-state mRNA levels of neuroendocrine markers such as neurotensin (NTS), neuroendocrine-specific protein (NSP), neural cell adhesion molecule 1 (NCAM1) and gamma-aminobutyric acid B-type receptor (GPR51) in cell line H460-M. Semaphorin 3B (SEMA3B) was dramatically down-regulated in cell line H460-M and emerged as the most interesting gene for target validation.

Carcinoma, Large Cell↗

PubMed2003

Strategic Research Institute--first international siRNA conference. Prospect for new therapeutics and commercial opportunities for pharma and biotech. 24-25 March 2003, LaJolla, CA, USA.

Small interfering RNAs (siRNAs), with their power to selectively silence genes, have gained much attention from biotech and pharmaceutical companies and investors. Key players in the field, from innovative biotech start-ups to big pharmaceutical companies, gathered at Strategic Research Institute's First International siRNA conference in the scenic Hilton La Jolla Torrey Pines. Topics addressed ranged from the latest technology advances and applications of RNA interference (RNAi) in drug discovery, to critical business issues such as intellectual property portfolio strategy and market prospects. While RNAi is indisputably accepted as a powerful tool in target validation and functional genomics, the concept of an siRNA drug is still viewed by big pharma companies as next-generation therapeutics. Yet challenges seem tractable. Several companies, such as Ribozyme Pharmaceuticals Inc, Alnylam Pharmaceuticals and Intradigm Corp, are working hard to prove that the bigger companies are being too conservative. The conference provided a clear vision of RNAi in drug discovery today, its potential and remaining challenges.

Animals↗

PubMed2003

Antibody like peptidomimetics as large scale immunodetection probes.

Antibodies are often used to study the molecular basis of physiologic processes. Despite the widespread applications of monoclonal antibodies (mAb) from basic science to successful therapeutics in clinical settings their use is limited. Production of mAb is often cumbersome and creating diverse and therapeutic amounts of useful mAb is difficult. We have developed a methodology to reduce an antibody into much smaller peptidomimetics and have engineered the mimetics for increased serum half life and affinity. The novel species are termed "antibody like binding peptidomimetics" (ABiP). We developed the Anti-Her2/neu peptidomimetic (AHNP) which is a mimic of Herceptin, a mAb used for advanced breast cancer therapy. The AHNP has been used as a defining tool to develop immunodetection probes that exemplify a general process application. AHNP has been expressed as an oligomeric fusion protein with streptavidin. These Herceptin like ABiPs were used to detect the Her2/neu antigen at extremely low concentrations using the immunodetection amplification technique (IDAT) which our laboratory has also developed. A fully developed highly diverse library of ABiPs represents an alternative for panels of monoclonal antibodies and may also be useful for target validation, antigen detection, therapeutics and as a platform for drug development.

Animals↗

PubMed2003

Silicon chemistry as a novel source of chemical diversity in drug design.

The use of organosilicon chemistry in drug design is reviewed. The field of bioorganosilicon chemistry, which sprung up in the 1970s to exploit the opportunities of silicon for drug design, is currently being developed into a practical and commercial enterprise. This review is mainly focused on two different approaches: (i) synthesizing a silicon analog of a known drug in which one carbon atom has been replaced by a silicon atom, with the rest of the molecule being identical (carbon/silicon switch, sila-substitution); (ii) synthesizing completely new silicon-based classes of compounds (the carbon analogs of which do not exist) that exploit specific features of silicon chemistry to address a well-validated target.

Amino Acids↗

PubMed2004

Oligonucleotide therapeutics: 25 years agrowing.

The year 2003 saw the 25th anniversary of the first publication of research using antisense oligonucleotides in cells. Oligonucleotides complementary to RNA use a variety of mechanisms to provide a direct link from genomics to gene function, drug target validation and new lead therapeutics. Other applications use oligonucleotides that bind to DNA or proteins to serve similar purposes. In this review, recent advances in mechanisms, chemical modifications and uses of oligonucleotides are discussed, and a broad overview of progress, mainly concerning RNA inhibition, is provided.

ATP-Binding Cassette Transporters↗

PubMed2004

In silico selection of functional RNA molecules.

Ribonucleic acid (RNA) molecules combine the coding potential of deoxyribonucleic acid (DNA) with various outwardly visible functions. RNA can be considered as a molecular unit of genotype and phenotype, and this concept has led to the hypothesis of a prebiotic world entirely dominated by RNA. In the postbiotic world, RNA is involved in all of the vital steps of information transfer from genes to gene products, and might intervene in gene expression and many other biological functions, either positively or negatively. RNA molecules have demonstrated tremendous potential as drug targets and drug candidates in the pharmaceutical and biotechnology industries, and are key components in a number of important processes, including microarray-based transcriptome analyses, functional target validation using antisense nucleic acids or short-interfering RNA (siRNA), and RNA-based drug development. The success of these significant but costly processes depends upon intelligent functional RNA design and the development of high-throughput compatible in silico selection tools and filters.

Animals↗

PubMed2004

Apoptotic responsiveness of PC-3 prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand: evidence for differential effects of Bcl-xL and Bcl-2 down-regulation.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is cytotoxic to the majority of cancer cells while sparing most normal cells. However, different prostate carcinoma cell lines respond with different sensitivities to TRAIL, urging us to disclose the mechanisms that determine TRAIL sensitivity in prostate cancer cells, i.e. to identify and validate target molecules. In this report, we show that down-regulation ('knockdown') of Bcl-xL, but not Bcl-2, markedly amplifies TRAIL-induced apoptosis in PC-3 prostate carcinoma cells. The knockdown was accomplished by second-generation chimeric antisense oligonucleotides: Bcl-2 and Bcl-xL levels were strongly and reproducibly reduced, as revealed by real-time RT-PCR and Western blot analyses. Knockdown of Bcl-xL and administration of TRAIL significantly synergized in dissipation of mitochondrial membrane potential, release of cytochrome c, activation of caspase-9 and -3 and, consequently, apoptotic cell death. Knockdown of Bcl-2 did not affect any of these activities. We conclude that that Bcl-xL represents a promising target to improve cancer therapy by potentiating TRAIL's cytotoxic effects.

Apoptosis↗

PubMed2004

LNA-antisense rivals siRNA for gene silencing.

Locked nucleic acid (LNA) is a class of nucleic acid analogs possessing unprecedented binding affinity toward complementary DNA and RNA while obeying the Watson-Crick base-pairing rules. For efficient gene silencing in vitro and in vivo, fully modified or chimeric LNA oligonucleotides have been applied. LNA oligonucleotides are commercially available, can be transfected using standard techniques, are non-toxic, lead to increased target accessibility, can be designed to activate RNase H, and function in steric block approaches. LNA-Antisense, including gapmer LNA containing a central DNA or phosphorothioate-DNA segment flanked by LNA gaps, rivals siRNA as the technology of choice for target validation and therapeutic applications.

Animals↗

PubMedDate not supplied

CNS drug discovery: challenges and solutions.

The worldwide market for therapies for central nervous system (CNS) disorders was valued at around US dollars 50 billion in 2001, and is set to grow sharply in the years ahead. This is because of a marked increase in the number of people aged over 65 (the "baby boomer" effect), which will lead to increased demand for more safe and effective medicines for CNS disorders. This one-day Society for Medicines Research symposium, held September 23, 2004, in London, United Kingdom, was organized by Dr. Alan M. Palmer (Pharmidex, London, U.K.) and Prof. F. Anne Stephenson (School of Pharmacy, University of London, U.K.). More than 100 delegates heard a scholarly and comprehensive review of the challenges currently facing CNS research and development, which was accompanied by consideration of a variety of innovative solution strategies. The meeting considered: 1) how to identify and validate targets for potential CNS drugs; 2) how to assess brain penetration (both in vitro and in vivo); 3) how to develop in silico methodologies to predict blood-brain barrier penetration; 4) how to assess therapeutic efficacy (both in vitro and in vivo); 5) how to establish reliable biomarkers to guide decision making; and 6) how to effectively apply magnetic resonance imaging to CNS drug discovery.

Animals↗

PubMed2005

The yin and yang of cancer therapeutics.

In this review, a potential theoretical framework for cancer therapeutics is presented, based on two concepts. The first concept considers cancer as a 'disease process' involving key regulatory pathways, and is discussed along with recent evidence and topics of special interest such as the combination of molecular diagnostics with developmental therapeutics. The second concept is the binary state concept of 'active/inactive' that seeks more relevant targets within the global molecular matrix of any given cancer. Here, these concepts are considered, along with the growing body of evidence that supports them. The 'binary' concept may facilitate both target selection and target validation.

Animals↗

PubMed2005

Modulation of gene expression by siRNA in hematopoietic cells.

RNA interference (RNAi) has been established as a powerful tool for identifying gene function in many biological processes and can be used for genome-wide functional genetic screens in mammalian cells. For such purposes, expression cassettes encoding RNAi triggers can be efficiently introduced into the host cell genome utilizing viral vector systems, resulting in long-term silencing of target gene expression. Transient gene silencing can also be induced by exogenous delivery of suitable RNAi triggers to target cells. However, similarly to other reverse genetic tools, there are technical challenges and limitations associated with RNAi, some of which are specific to hematopoietic cells. In this review we discuss the rational design of effective RNAi triggers, different approaches for their efficient delivery, and the value of RNAi both as a potential therapeutic strategy and as a tool for functional genomics and target validation in hematopoietic cells.

Animals↗

PubMed2005

Use of high-content analysis for compound screening and target selection.

High-content analysis (HCA) has rapidly established itself as a core technology in drug discovery for secondary cell-based screening. When combined with our knowledge of genetics, HCA can provide a powerful tool for target validation, but excitingly, HCA may also enable the increased use of cellular assays in high-throughput screening for novel drug leads.

Animals↗

PubMed2005

Chemical genetic approaches to kinase drug discovery.

Chemical genetics is an important approach in biological research that utilizes small molecules to study protein function. In the context of kinase drug discovery, chemical genetics has broad applications in identifying and validating targets, demonstrating the druggability of a target and providing potential kinase inhibitor leads for further optimization. The successful application of this approach demands that the small-molecule kinase inhibitors used achieve a desired potency and selectivity. However, given the high number (> 518) and homology of kinases in the human genome, identifying potent and selective kinase inhibitors presents a major challenge. This article reviews recent advances in small-molecule kinase inhibitor design, with an emphasis on selectivity, and also discusses recent progress in the development of analog-sensitive kinase allele (ASKA)-based chemical genetics technology, which creates genetically engineered versions of protein kinases that are fully functional and can be selectively inhibited by a unique reference orthogonal inhibitor. Examples of how ASKA technology can be applied to kinase drug discovery is discussed.

Animals↗

PubMed2005

Recent advances in heterocycle generation using the efficient Ugi multiple-component condensation reaction.

The current trend of rising research spending and falling numbers of novel chemical entities continues to drive efforts aimed at increasing efficiency in the drug discovery process. Strategic issues, such as assigning resources to poorly validated targets have been implicated in the declining productivity of recent years. Tactical approaches employed to improve this situation include attempts to speed the discovery process toward decision points in a timely manner. Accelerating the optimization of high-throughput screening hits is a goal in streamlining the discovery process, and the use of multiple-component condensation (MCC) reactions have proved useful toward this end. MCC reactions are powerful and efficient tools for the generation of diverse compound sets. Collections of compounds can be synthesized with all of the required diversity elements included in a single synthetic step. One of the most widely investigated MCC reactions is the Ugi four-component condensation. This review highlights disclosures of the Ugi reaction published over the past two years (2003 to 2005) in three areas: (i) Ugi reaction in conjunction with post-condensation cyclization; (ii) bifunctional condensations leading to heterocyclic cores; and (iii) general findings relating to linear products or interesting improvements in the basic Ugi reaction.

Automation↗

PubMed1991

Growth responses in the arterial wall.

Arterial structural changes play a key role in atherosclerosis and hypertension and could become a valid target for pharmacotherapy of these disorders. Current insights in arterial growth control were derived from experiments in cell culture and in experimental animals. In this study, we evaluated growth responses in isolated arterial segments and compared our in vitro observations to arterial changes in experimental models of essential and secondary renal hypertension. In isolated renal artery segments, serum growth factors caused a transient stimulation of DNA synthesis in the arterial media. This in vitro growth response did not lead to media hyperplasia, hypertrophy or hyperploidy. In intact, conscious 6-week-old spontaneously hypertensive rats (SHR), DNA synthesis in the media of large arteries was two to four times larger than that in arteries of age-matched normotensive rats. Yet, the elevated wall/lumen ratio in renal arteries of adult SHR was due to a reduction of the arterial lumen diameter and not to an altered media cross-sectional area. In addition, while aorta-coarctation resulted in a marked increase of renal arterial cross-sectional area it did not alter the number of renal artery smooth muscle cells. These observations indicate that even powerful chemical and mechanical mitogenic conditions do not alter the number of medial smooth muscle cells. This could be due to rapid down-regulation of arterial growth responsiveness, migration, and turnover of cells.

Animals↗

PubMed1988

Structural studies of the acquired immunodeficiency syndrome virus reverse transcriptase.

The clinical success of zidovudine has established the human immunodeficiency virus (HIV) reverse transcriptase (RT) as a valid target for the design of drugs to treat acquired immunodeficiency syndrome. In order to facilitate structural studies of this enzyme, expression systems in Escherichia coli, which allow the production of large amounts of RT, have been established. Using this recombinant material the RT has been purified and crystallized. Crystallographic studies currently underway are aimed at elucidating the three-dimensional structure of HIV RT. The availability of a bacterial expression system has enabled structural/functional studies of the RT by site-directed mutagenesis. These studies have identified amino acid residues that are essential for activity of the enzyme and might be involved in substrate binding. It is hoped that structural information of this nature will allow the rational design of HIV RT inhibitors.

Antiviral Agents↗

PubMed1998

[Trends of genomic researches for drug discoveries].

In drug discoveries it becomes more important to search and validate target genes that control diseases. The development of novel strategies for functional genomics is indispensable for large scale analysis of human genes. (1) Recently, several research projects sequencing 5'-end of full-length enriched cDNA libraries were started because most of expressed sequence tags(ESTs) lack the 5'-end information of mRNA that is necessary for identifying the correct coding region. (2) New key technologies to quantify numerous gene expression levels simultaneously are now in progress. (3) Toward the functional analysis of unpredictable human genes, new strategies by using model animals (mouse, yeast, nematode) are under construction. Advances in molecular genetics and functional genomics will create new challenges for both drug discoveries and clinical evaluations.

Animals↗

PubMed2003

Chemical genomics-based target identification and validation of anti-angiogenic agents.

The recent use of chemical genomics to identify bioactive small molecules that interact with specific proteins has had a tremendous impact on both the functional analysis of genes and drug development. Accordingly, the current review focuses on the utilization of this new research engine in the target identification and validation of anti-angiogenic agents capable of regulating the growth and spread of cancer cells. In addition, the use of chemical genomics to discover novel anti-angiogenic agent targets and to validate their biological relevancy is providing new insights into the biological role of targets in angiogenesis as well as advancing the development of new anti-angiogenic agents.

Angiogenesis Inhibitors↗