An analysis of the attrition of drug candidates from four major pharmaceutical companies.

The pharmaceutical industry remains under huge pressure to address the high attrition rates in drug development. Attempts to reduce the number of efficacy- and safety-related failures by analysing possible links to the physicochemical properties of small-molecule drug candidates have been inconclusive because of the limited size of data sets from individual companies. Here, we describe the compilation and analysis of combined data on the attrition of drug candidates from AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer. The analysis reaffirms that control of physicochemical properties during compound optimization is beneficial in identifying compounds of candidate drug quality and indicates for the first time a link between the physicochemical properties of compounds and clinical failure due to safety issues. The results also suggest that further control of physicochemical properties is unlikely to have a significant effect on attrition rates and that additional work is required to address safety-related failures. Further cross-company collaborations will be crucial to future progress in this area.

A high content screening assay for identifying lysosomotropic compounds.

Lysosomes are acidic organelles that are essential for the degradation of old organelles and engulfed microbes. Furthermore, lysosomes play a key role in cell death. Lipophilic or amphiphilic compounds with a basic moiety can become protonated and trapped within lysosomes, causing lysosomal dysfunction. Therefore, high-throughput screens to detect lysosomotropism, the accumulation of compounds in lysosomes, are desirable. Hence, we developed a 96-well format, high content screening assay that measures lysosomotropism and cytotoxicity by quantitative image analysis. Forty drugs, including antidepressants, antipsychotics, antiarrhythmics and anticancer agents, were tested for their effects on lysosomotropism and cytotoxicity in H9c2 cells. The assay correctly identified drugs known to cause lysosomotropism and revealed novel information showing that the anticancer drugs, gefitinib, lapatinib, and dasatinib, caused lysosomotropism. Although structurally and pharmacologically diverse, drugs that were lysosomotropic shared certain physicochemical properties, possessing a ClogP>2 and a basic pKa between 6.5 and 11. In contrast, drugs which did not lie in this physicochemical property space were not lysosomotropic. The assay is a robust, rapid screen that can be used to identify lysosomotropic, as well as, cytotoxic compounds, and can be positioned within a screening paradigm to understand the role of lysosomotropism as a contributor to drug-induced toxicity.

Custom cDNA microarrays; technologies and applications.

Technologies designed to characterise genes and their products on a discovery scale are now having an impact on many areas of biology, including toxicology. A number of platforms exist which measure changes in expression of potentially thousands of genes simultaneously. These approaches, when applied to toxicology, are termed 'toxicogenomics' and promise to greatly facilitate mechanism-based research on toxicant action with the longer term possibility of assisting in the identification of potential toxicity issues earlier in the development of new pharmaceutical, agrochemical and chemical products. An example of such a platform developed in our laboratory is ToxBlot II, a custom microarray containing cDNAs representing 12564 human genes chosen on the basis of their potential relevance to a broad range of toxicities. ToxBlot II can assist in characterising many outcomes including processes as diverse as immune system response, receptor biology, signal transduction, protein modification, membrane transport, growth and development, metabolism, oxidative stress and regulation of the cell cytoskeleton. Furthermore, ToxBlot II allows the simultaneous expression profiling of genes representing entire cellular pathways, facilitating a very detailed investigation of potential mechanisms of toxicity. Our laboratory is applying this and other custom microarrays to many areas of toxicology, including endocrine disruption, receptor biology, stress response and the effect of toxicants on immune function. Such approaches can be particularly valuable when used in conjunction with 'functional genomics' such as transgenic or knockout models.

Use of genomics in toxicology and epidemiology: findings and recommendations of a workshop.

The sequencing of the human genome has revolutionized biology and led to an astounding variety of technologies and bioinformatics tools, enabling researchers to study expression of genes, the function of proteins, metabolism, and genetic differences within populations and between individuals. These scientific advances are making an impact in the medical research community and hold great promise for prevention, diagnosis, and treatment of diseases. This developing field also holds great promise for improving the scientific basis for understanding the potential impacts of chemicals on health and the environment. A workshop sponsored by the International Council of Chemical Associations was held to review the state of the science in the application of genomics technologies in toxicology and epidemiology. Further, consideration was given to the ethical, legal, and regulatory issues and their influence on the direction and application of genomics technologies to environmental health research. Four overarching themes emerged from the workshop: Genomics technologies should be used within a framework of toxicology and epidemiology principles and applied in a context that can be used in risk assessment; effective application of these technologies to epidemiology will require suitable biologic samples from large and diverse population groups at the relevant period of exposure; ethical, legal, and social perspectives require involvement of all stakeholder communities; and a unified research agenda for genomics technologies as applied to toxicology, epidemiology, and risk assessment is urgently needed for the regulatory and scientific communities to realize the potential power and benefits of these new technologies.