The drug discovery process starts with the identification of a molecular target which is involved in disease progression. A target is a broad term which can include proteins, genes and RNA.
A good target needs to be efficacious, safe, meet clinical and commercial needs and above all be “druggable”.
Once identified, the target is tested (ie. ability to regulate biological processes, association with a specific disease) to demonstrate that it is a therapeutically relevant pharmacological target.
Target validation confirms that manipulating the molecular target can produce the desired change in behaviour of diseased cells.
Upon validation of the target, primary assays aimed at identifying potential hits are developed. High throughput compound screening assays against the target of interest can lead to identification of initial hit compounds.
Those initial hits can be re-tested to validate their on-target activity. Finally, hits or hit series are ranked to select the most promising for the hit-to-lead phase.
This step aims at refining the top hit series to identify and generate selective compounds with improved potency, reduced off-target activities and adequate pharmacokinetics properties for later in vivo efficacy models. Preliminary medicinal chemistry efforts are made at this stage to design and synthesize new analogues based on the hit series to quickly determine potential structure-activity relationships (SARs).
An early assessment of Absorption-Distribution-Metabolism-Excretion (ADME) properties is also performed on those hits or hit series so that lead compounds can be prioritized early in the process.
Lead compounds generated at the HTL phase are optimized here to make them more effective and safer. More intense SAR effort is put around the top leads or lead series to generate hundreds of differents variations or analogues thereof.
Chemists and biologists work closely together to make those analogues and immediately test and re-test them in biological assays.
At the pre-clinical stage, some critical points are addressed in more detail, i.e. tolerability and potential side effects, optimal pharmaceutical formulation, PK and toxicity studies. The result is a candidate compound ready to be used in humans.
Clinical development and proof-of-concept trial rely on the early implication of clinicians in the drug development process to provide a clinically-oriented development strategy. The availability of human samples for translational studies also enables an accurate estimation of therapeutic efficacy, allows a rapid pharmacological refinement of therapeutic targets and facilitates the identification of the best therapeutic strategy.