Maintaining research and development (R&D) productivity at a sustainable level is one of the main challenges currently facing the pharmaceutical industry. In this article, we discuss the results of a ...comprehensive longitudinal review of AstraZeneca's small-molecule drug projects from 2005 to 2010. The analysis allowed us to establish a framework based on the five most important technical determinants of project success and pipeline quality, which we describe as the five 'R's: the right target, the right patient, the right tissue, the right safety and the right commercial potential. A sixth factor - the right culture - is also crucial in encouraging effective decision-making based on these technical determinants. AstraZeneca is currently applying this framework to guide its R&D teams, and although it is too early to demonstrate whether this has improved the company's R&D productivity, we present our data and analysis here in the hope that it may assist the industry overall in addressing this key challenge.
More than 90% of the compounds that enter clinical trials fail to demonstrate sufficient safety and efficacy to gain regulatory approval. Most of this failure is due to the limited predictive value ...of preclinical models of disease, and our continued ignorance regarding the consequences of perturbing specific targets over long periods of time in humans. 'Experiments of nature' - naturally occurring mutations in humans that affect the activity of a particular protein target or targets - can be used to estimate the probable efficacy and toxicity of a drug targeting such proteins, as well as to establish causal rather than reactive relationships between targets and outcomes. Here, we describe the concept of dose-response curves derived from experiments of nature, with an emphasis on human genetics as a valuable tool to prioritize molecular targets in drug development. We discuss empirical examples of drug-gene pairs that support the role of human genetics in testing therapeutic hypotheses at the stage of target validation, provide objective criteria to prioritize genetic findings for future drug discovery efforts and highlight the limitations of a target validation approach that is anchored in human genetics.
•An unprecedented number of peptide therapeutics have recently been approved.•Clinical pipeline analysis reveals an emphasis on peptides with enhanced properties.•Development of innovative ...glucagon-like peptide (GLP)-1 receptor agonists is a strong growth area.•Peptide–drug conjugates and constrained peptides hold promise as new therapeutics.
The notable expansion of peptide therapeutics development in the late 1990s and the 2000s led to an unprecedented number of marketing approvals in 2012 and has provided a robust pipeline that should deliver numerous approvals during the remainder of the 2010s. To document the current status of the pipeline, we collected data for peptide therapeutics in clinical studies and regulatory review, as well as those recently approved. In this Foundation review, we provide an overview of the pipeline, including therapeutic area and molecular targets, with a focus on glucagon-like peptide 1 receptor agonists. Areas for potential expansion, for example constrained peptides and peptide–drug conjugates, are profiled.
The unprecedented number of marketing approvals in 2012 for peptide therapeutics could be a harbinger for the innovative peptide-based drugs in the clinical pipeline.
Display omitted
A long history of use and extensive documentation of the clinical practices of traditional Chinese medicine resulted in a considerable number of classical preparations, which are ...still widely used. This heritage of our ancestors provides a unique resource for drug discovery. Already, a number of important drugs have been developed from traditional medicines, which in fact form the core of Western pharmacotherapy. Therefore, this article discusses the differences in drug development between traditional medicine and Western medicine. Moreover, the article uses the discovery of artemisinin as an example that illustrates the “bedside–bench–bedside” approach to drug discovery to explain that the middle way for drug development is to take advantage of the best features of these two distinct systems and compensate for certain weaknesses in each. This article also summarizes evidence-based traditional medicines and discusses quality control and quality assessment, the crucial steps in botanical drug development. Herbgenomics may provide effective tools to clarify the molecular mechanism of traditional medicines in the botanical drug development. The totality-of-the-evidence approach used by the U.S. Food and Drug Administration for botanical products provides the directions on how to perform quality control from the field throughout the entire production process.
Piplartine (piperlongumine, 5,6-dihydro-1-(2E)-1-oxo-3-(3,4,5-trimethoxyphenyl)-2-propenyl-2(1H)-pyridinone) is a biologically active alkaloid/amide from peppers, as from long pepper (Piper longum L. ...– Piperaceae). Long pepper is one of the most widely used in Ayurvedic medicine, which is used to treat many diseases, including tumors. The purpose of the current paper is to address to the chemical structure establishment and to systematically survey the published articles and highlight recent advances in the knowledge of the therapeutic potential of piplartine, establishing new goals for future research. The reported pharmacological activities of piplartine include cytotoxic, genotoxic, antitumor, antiangiogenic, antimetastatic, antiplatelet aggregation, antinociceptive, anxiolytic, antidepressant, anti-atherosclerotic, antidiabetic, antibacterial, antifungal, leishmanicidal, trypanocidal, and schistosomicidal activities. Among the multiple pharmacological effects of piplartine, its anticancer property is the most promising. Therefore, the preclinical anticancer potential of piplartine has been extensively investigated, which recently resulted in one patent. This compound is selectively cytotoxic against cancer cells by induction of oxidative stress, induces genotoxicity, as an alternative strategy to killing tumor cells, has excellent oral bioavailability in mice, inhibits tumor growth in mice, and presents only weak systemic toxicity. In summary, we conclude that piplartine is effective for use in cancer therapy and its safety using chronic toxicological studies should be addressed to support the viability of clinical trials.
Display omitted
Andrographis paniculata has long been part of the traditional herbal medicine system in Asia and in Scandinavia. Andrographolide was isolated as a major bioactive constituent of A. ...paniculata in 1951, and since 1984, andrographolide and its analogs have been scrutinized with modern drug discovery approach for anti-inflammatory properties. With this accumulated wealth of pre-clinical data, it is imperative to review and consolidate different sources of information, to decipher the major anti-inflammatory mechanisms of action in inflammatory diseases, and to provide direction for future studies. Andrographolide and its analogs have been shown to provide anti-inflammatory benefits in a variety of inflammatory disease models. Among the diverse signaling pathways investigated, inhibition of NF-κB activity is the prevailing anti-inflammatory mechanism elicited by andrographolide. There is also increasing evidence supporting endogenous antioxidant defense enhancement by andrographolide through Nrf2 activation. However, the exact pathway leading to NF-κB and Nrf2 activation by andrographolide has yet to be elucidated. Validation and consensus on the major mechanistic actions of andrographolide in different inflammatory conditions are required before translating current findings into clinical settings. There are a few clinical trials conducted using andrographolide in fixed combination formulation which have shown anti-inflammatory benefits and good safety profile. A concerted effort is definitely needed to identify potent andrographolide lead compounds with improved pharmacokinetics and toxicological properties. Taken together, andrographolide and its analogs have great potential to be the next new class of anti-inflammatory agents, and more andrographolide molecules are likely moving towards clinical study stage in the near future.
The signal transducer and activator of transcription (STAT) proteins have important roles in biological processes. The abnormal activation of STAT signalling pathways is also implicated in many human ...diseases, including cancer, autoimmune diseases, rheumatoid arthritis, asthma and diabetes. Over a decade has passed since the first inhibitor of a STAT protein was reported and efforts to discover modulators of STAT signalling as therapeutics continue. This Review discusses the outcomes of the ongoing drug discovery research endeavours against STAT proteins, provides perspectives on new directions for accelerating the discovery of drug candidates, and highlights the noteworthy candidate therapeutics that have progressed to clinical trials.
Cystic fibrosis is a fatal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Two main categories of drugs are being developed: correctors that improve ...folding of CFTR and potentiators that recover the function of CFTR. Here, we report two cryo-electron microscopy structures of human CFTR in complex with potentiators: one with the U.S. Food and Drug Administration (FDA)-approved drug ivacaftor at 3.3-angstrom resolution and the other with an investigational drug, GLPG1837, at 3.2-angstrom resolution. These two drugs, although chemically dissimilar, bind to the same site within the transmembrane region. Mutagenesis suggests that in both cases, hydrogen bonds provided by the protein are important for drug recognition. The molecular details of how ivacaftor and GLPG1837 interact with CFTR may facilitate structure-based optimization of therapeutic compounds.
There is a wide variety of cancer types yet, all share some common cellular and molecular behaviors. Most of the chemotherapeutic agents used in cancer treatment are designed to target common ...deregulated mechanisms within cancer cells. Many healthy tissues are also affected by the cytotoxic effects of these chemical agents. Fucoidan, a natural component of brown seaweed, has anti-cancer activity against various cancer types by targeting key apoptotic molecules. It also has beneficial effects as it can protect against toxicity associated with chemotherapeutic agents and radiation. Thus the synergistic effect of fucoidan with current anti-cancer agents is of considerable interest. This review discusses the mechanisms by which fucoidan retards tumor development, eradicates tumor cells and synergizes with anti-cancer chemotherapeutic agents. Challenges to the development of fucoidan as an anti-cancer agent will also be discussed.
The role of inflammation in the pathogenesis of type 2 diabetes and associated complications is now well established. Several conditions that are driven by inflammatory processes are also associated ...with diabetes, including rheumatoid arthritis, gout, psoriasis and Crohn's disease, and various anti-inflammatory drugs have been approved or are in late stages of development for the treatment of these conditions. This review discusses the rationale for the use of some of these anti-inflammatory treatments in patients with diabetes and what we could expect from their use. Future immunomodulatory treatments may not target a specific disease, but could instead act on a dysfunctional pathway that causes several conditions associated with the metabolic syndrome.
PDF
