Many drugs fail during the various stages of clinical development either because they are not effective, or because they are toxic. This is often the consequence of a poor pre-clinical validation of the target: therefore, target validation (TV) is a crucial step on the path of drug discovery and development. The goal of a target validation effort is to demonstrate that the biological target plays a critical role in the disease process, and that modulation of the target itself can exert a therapeutic effect in the absence of toxicity on normal cells and tissues.
At IRBM, our industry-seasoned scientists work in the TV space with an unbiased approach: our goal is to work with you to demonstrate the disease relevance of your target and to elucidate its druggable attributes, i.e. the probability of finding a selective molecule for proof-of-concept pharmacological studies in a timely manner. The early target TV process requires multiple efforts, ranging from genetic manipulation of the target in relevant cells, to interrogation of the consequence of target manipulation on pathways downstream the target and to -omics profiling in appropriate cell systems or in vivo models.
A successful preliminary TV is the pre-requisite to start a drug discovery program centered on your target but the entire TV process continues during the early stages of the drug development to generate very strong evidence for MOA-based efficacy and to characterize MOA-based toxicity. These efforts can include the generation of chemical probes, i.e. compounds with sufficient potency, selectivity and specificity for the target but with largely suboptimal pharmacological properties to perform early POC studies. Depending on the target, additional studies can include, but not be limited to, the generation of more predictive models, the generation in vitro and/or in cells of drug-resistant mutants of the target, and the identification of the appropriate biomarkers to monitor the effect of target modulation in vitro and in vivo.
We can advance your projects with our cross-functional project teams according to a comprehensive work plan, quickly moving to Go/No-Go decision points where project potential and risk mitigation are discussed through objective evaluation. Potential issues surrounding a target are also assessed upfront including anticipated toxicological consequences of inhibiting a target in normal cells, and role of related protein family members in normal physiology. Predefined decision points are incorporated into comprehensive workplan to allow for calculated risk to be built into programs and to provide early exit points if a program is showing unanticipated and non- addressable issues. These work plans and decision points can help you to take the right decision and the right time to focus your resources and time of the programs with the highest probability of success (POS).