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.
Modern drug discovery involves the identification of screening hits, medicinal chemistry, and optimization of those hits to increase the affinity, selectivity, efficacy/potency, metabolic stability, and bioavailability. INDIGO’s kits and services are ideal for drug discovery because they provide a convenient way to examine a compound for its ability to regulate nuclear receptor activity in agonist, inverse-agonist, or antagonist mode.
Using our robust cell-based reporter assays and nuclear receptor expertise allows you to better identify and prioritize drug leads. INDIGO’s research lab can aid in the identification of targets of interest and help your research with complimentary study consults and design. The INDIGO team can also aid in reducing the number of viable leads with high-throughput screening of compounds for efficacy and potency. Our scientists aim to get you to the next phase of discovery faster and prevent unnecessary steps backward by providing the most comprehensive data for your investment with fast turnaround times.
Whether you are just beginning the drug discovery process, or have narrowed down viable leads using INDIGO’s services or through your own effort, INDIGO’s cell-based assays allow you to examine a compounds efficacy and potency in cells, in your own lab, with assay data ready in just 24 hours. Our cell-based reporter assays are designed to quantify nuclear receptor activity with clear, reproducible data lot-to-lot. This allows for the prioritization of leads by learning the efficacy of a compound in vitro, as well as to establish the EC50/IC50 values and potential recommended dosing levels. This can be done with human receptors as well as those of orthologs to decide which animal model would be best for in vivo animal trials.
INDIGO's research services and assay kits provide a convenient way to examine your compound's ability to regulate nuclear receptor activity in robust, cell-based reporter assays.
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.