Cell-based apoptosis assays in oncology drug discovery

Importance of the field: Screening compounds with a cell-based phenotypic approach complements target-based discovery programs because of the opportunity to investigate targets in the context of the cellular milieu and to discover novel targets.

Areas covered in this review: Utilizing a cell-based apoptotic phenotype screen for discovery and optimization of apoptosis inducers and affirming activity as potential anticancer agents in vivo with xenograft models. Subsequently, chemical genetic tools are utilized to identify and validate previously unrecognized cancer targets. Case studies showing the various multidisciplinary approaches utilized for several years are reviewed.

What the reader will gain: The interactive nature of the drug and target discovery processes, and insights that come from integration of cellular biology, medicinal chemistry and animal research.

Take home message: Phenotype proapoptotic screen followed by chemical genetics is useful for anticancer drug research, for the discovery of potential drugs and identification of druggable targets.     

Cell-based apoptosis assays in oncology drug discovery

Importance of the field: Screening compounds with a cell-based phenotypic approach complements target-based discovery programs because of the opportunity to investigate targets in the context of the cellular milieu and to discover novel targets. Areas covered in this review: Utilizing a cell-based apoptotic phenotype screen for discovery and optimization of apoptosis inducers and affirming activity as potential anticancer agents in vivo with xenograft models. Subsequently, chemical genetic tools are utilized to identify and validate previously unrecognized cancer targets. Case studies showing the various multidisciplinary approaches utilized for several years are reviewed. What the reader will gain: The interactive nature of the drug and target discovery processes, and insights that come from integration of cellular biology, medicinal chemistry and animal research. Take home message: Phenotype proapoptotic screen followed by chemical genetics is useful for anticancer drug research, for the discovery of potential drugs and identification of druggable targets.     

Overview of precision oncology trials: challenges and opportunities

Introduction: In recent years, the therapeutic management of selected patients with cancer has shifted toward the ‘precision medicine’ approach based on patient’s mechanisms of tumorigenesis, and their baseline characteristics and comorbidities. Complete tumor and cell-free DNA profiling using next-generation sequencing, proteomic and RNA analysis, and immune mechanisms should to be taken into consideration and accurate bioinformatic analysis is essential to optimize patient’s treatment.

Areas covered: The challenges and opportunities of conducting clinical trials in precision oncology are summarized.

Expert commentary: Precision medicine has significantly changed the diagnostic and therapeutic landscape of cancer. Successful implementation of precision medicine requires translational and bioinformatics infrastructure to support optimization of treatment selection. Targeted therapy, immunotherapy, T-cell therapy alone or in combination with cytotoxic or other effective therapeutic strategies and innovative clinical trials with adaptive design should be offered to all patients. Data sharing and ‘N-of-1’ models hold the promise to optimize the treatment of individual patients and expedite drug approval for rare alterations and tumor types. Artificial intelligence will facilitate accurate utilization of sequencing data to perform algorithm analysis. Collaboration of healthcare providers with pharmaceutical and biotechnical companies, scientific organizations, and governmental regulatory agencies have a crucial role in curing cancer.     

Ageing and metabolism: drug discovery opportunities

There has recently been significant progress in our understanding of the mechanisms that regulate ageing, and it has been shown that changes in single genes can dramatically extend lifespan and increase resistance to many diseases. Furthermore, many of these genes belong to evolutionarily conserved pathways that also control energy metabolism. In this review, we describe the shared molecular machinery that regulates ageing and energy metabolism. Although drugs to slow ageing face severe regulatory hurdles, it is likely that an understanding of ageing pathways will help to identify novel drug targets to treat metabolic disorders and other age-related diseases.     

Peptide and protein drug analysis by MS: challenges and opportunities for the discovery environment

Straightforward assay development using MS has become commonplace in most modern pharmaceutical laboratories. In particular, MS is an invaluable tool in the discovery environment of this industry, making it possible to characterize the structures of target drugs and to screen large numbers of potential drug candidates in metabolism and pharmacokinetics studies, and much more. Furthermore, as drug portfolios expand to include biotherapeutic species, such as peptides and proteins, MS is there to meet any analytical challenges. In this article, general aspects of MS in the discovery environment are discussed, as well as what the future might hold.     

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.     

Melanocortin receptors: new opportunities in drug discovery

The cloning of five different subtypes of melanocortin receptors, MC1-5, have provided new opportunities for the discovery of drugs that may be useful for the treatment of a variety of clinically important conditions, including MC1 receptor agonists for inflammatory diseases, MC3 receptor agonists for sexual dysfunctions and MC4 receptor agonists and antagonists for treatment of obesity, anorexia and drug abuse. This review discusses patents covering the cloning of the MC receptors, the endogenous MC receptor antagonists agouti signalling peptide and agouti related protein and novel compounds target towards the MC receptors.     

Data integration: challenges for drug discovery

The effective integration of data and knowledge from many disparate sources will be crucial to future drug discovery. Data integration is a key element of conducting scientific investigations with modern platform technologies, managing increasingly complex discovery portfolios and processes, and fully realizing economies of scale in large enterprises. However, viewing data integration as simply an 'IT problem' underestimates the novel and serious scientific and management challenges it embodies - challenges that could require significant methodological and even cultural changes in our approach to data.     

Opportunities and challenges in antiparasitic drug discovery

New antiparasitic drugs are urgently needed to treat and control diseases such as malaria, leishmaniasis, sleeping sickness and filariasis, which affect millions of people each year. However, because the majority of those infected live in countries in which the prospects of any financial return on investment are too low to support market-driven drug discovery and development, alternative approaches are needed. In this article, challenges and opportunities for antiparasitic drug discovery are considered, highlighting some of the progress that has been made in recent years, partly through scientific advances, but also by more effective partnership between the public and private sectors.     

Inflammation in atherosclerosis: new opportunities for drug discovery

Many lines of evidence indicate that inflammation is the ultimate cause of atherosclerosis; high cholesterol levels cause atherosclerosis through mechanism of inflammation. Drugs designed to address inflammatory aspects of atherosclerosis will likely be more effective than current therapies in treating and preventing coronary artery disease.     

Nanodiamond-mediated drug delivery and imaging: challenges and opportunities

Introduction: The field of nanoparticle-based therapeutic systems is rapidly expanding encompassing a wide variety of practices ranging from detection to diagnosis to treatment. Recently a great potential of nanodiamond (ND) particles as a multimodal imaging/therapy platform has been demonstrated.

Areas covered: This review describes a unique set of properties of ND particles attractive for drug delivery and imaging applications and highlights the most recent ND-based multimodal imaging/therapy approaches and related biocompatibility studies. The spectrum of major advancements includes marked improvements in tumor treatment efficacy and safety based on integration of ND with doxorubicin (DOX). Recent progress of ND-mediated drug delivery in orthopedic, dental and ophthalmic applications is also discussed.

Expert opinion: ND particles possess a unique set of properties attractive for drug delivery applications, including exceptional biocompatibility, large carrier capacity and versatile surface chemistry properties, which enhance drug binding and provide sustainable drug release. Other unique attributes of NDs embrace bright stable fluorescence based on crystallographic defects. A roadmap toward a clinical translation comprises identification of ND-therapeutic compounds that display marked improvements over clinical standards with respects to efficacy, safety and cost.