Toxicology in The Drug Discovery and Development Process
Toxicity continues to be a primary cause for compound attrition and long development timelines, causing companies to increasingly integrate safety assessment principles into earlier phases of the drug discovery process. A new discipline has emerged called Discovery Toxicology, which utilizes many in vitro tools to prioritize compounds at the earliest phases of drug discovery.
A typical testing scheme for a small molecule drug begins with large numbers of compounds and high-throughput assays. As the number of viable leads is reduced, incrementally more predictive but lower throughput assays identify those leads with the most drug-like properties and optimal in vitro and in vivo efficacy. Compounds that successfully meet preclinical efficacy, ADME, pharmacokinetics, and safety criteria are nominated as candidates for formal development.
Historically, within pharmaceutical companies the functions of discovery and development, including preclinical safety assessment, were performed by discreet organizations within the company. As toxicity continues to be a primary cause for compound attrition and long development cycle times, companies have increasingly integrated safety assessment principles into earlier phases of the drug discovery process, and a new discipline has emerged called Discovery Toxicology
INDIGO's approach to Discovery Toxicology is to provide research services to assist in prioritizing drug leads, found either through our Drug Discovery services or products, or through your own effort. We provide a series of in vitro assays in the broad categories of Prospective Screens, Safety Pharmacology, and Retrospective Screens.
For more information on the costs of the drug discovery process, check out our helpful infographic.
At INDIGO, we specialize in mechanistic and molecular toxicology, in particular those events related to Nuclear Receptors or other transcription factors, and offer prospective screens that predict potential adverse effects of your compounds of interest.
Drug-Drug Interactions NRs represent one of the most important families of drug targets, resulting from their roles as transcription factors and therefore regulators of gene expression and physiological functions. Since drug metabolism and transport proteins have several substrates, increases in the expression of these biotransformation systems may affect the activity of many drugs and nutrients, hence, drug-drug and drug-nutrient interactions. In particular, PXR and CAR have been implicated in affecting the expression of cytochrome P450s and other drug metabolism enzymes. INDIGO provides several NR assays that are predictive of potential liabilities due to drug-drug interactions.
Phenotypic Screens The INDIGO laboratory has extensive experience examining events that are downstream of nuclear receptor activation. Examples include quantification of gene expression by real-time PCR, adipogenesis assays, and gene expression microarrays. In addition, we can develop or utilize cell culture systems to examine the biological response of your compounds. Whether you start with your own RNA samples, tissues, or cells or utilize our cell culture service, INDIGO can design primers and quantify mRNA expression. More information on gene expression solutions from INDIGO.
Reporter Assay Panels Defining the system each receptor participates in can be approached in several ways such as sequence similarity, potential disease implication, or transcriptional networks. The latter is particularly helpful since it encompasses receptors to which there are no known endogenous ligands (orphan receptors) or have few selective pharmacologic agents to evaluate biological consequences. By choosing a select group of receptors to study, it is possible to better understand the biological and toxicological effects of your compounds. INDIGO has pre-designed several panels for you to choose, or you can talk to our experts to design your own panel of receptors.
Nuclear Receptor Profiling A major focus in the current discovery of drugs targeting nuclear receptors is identifying those with the highest selectivity and therefore lowest potential for off-target and unwanted effects. Due to regulation of metabolic enzymes by several nuclear receptors, there is increasing interest in understanding the potential of drug-drug and drug-nutrient interactions of potential drug leads. INDIGO provides a comprehensive list of optimized, robust, and selective whole-cell receptor assays, ideally suited for examining selectivity as well as potential interactions.
Retrospective screens are often done in response to a troubling finding in clinical studies such as hepatotoxicity in laboratory animals or unexpected failures in human trials. INDIGO's large portfolio of ortholog model assays can help determine if the enzyme induction response observed in laboratory animals is concordant with humans. Mouse, rat, dog, monkey, and/or zebrafish models are currently available for many receptors, with more available for custom development.