Developing a drug can take years and comes with significant costs. During the early phases of this journey, it is vital to have a robust process in place to allow rapid and informed decision-making. A fit-for-purpose drug screening cascade is core to this and this system must have the capability to test your hypotheses in biological systems to ensure you stay on the right course.
As you embark on designing an appropriate screening cascade, it is imperative to define the fundamental properties you seek in your prospective drug candidates. These attributes will significantly influence the selection of assays to be incorporated into your screening cascade. Questions such as the importance of selectivity for your target, whether you are targeting orthosteric or allosteric binding sites, the need for blood-brain barrier permeability, the specificity of target expression in certain cell types, and concerns about on-target toxicity must all be addressed early in the discovery process. Early discussions among your team are vital to ensure the right assays can be strategically implemented as your project progresses.
The primary objective of a screening cascade, or the design-make-test cycle, is to enable swift decision-making. Screening cascades evolve and adapt as molecules advance, and a cascade developed during the hit-to-lead phase may differ significantly from one in the lead optimisation phase. Nonetheless, at each stage, the cascade should swiftly provide answers to the most pressing questions facing the project team at that particular juncture. This rapid decision-making can accelerate compound progression, facilitate timely intellectual property filings for novel chemical matter, and, importantly, lead to cost savings in the long run. Recognising when to halt a program and reconsider the strategy is as crucial as striving to achieve key milestones.
Screening cascades can vary widely depending on the stage of drug discovery. In the following sections, we will outline key considerations for constructing an effective and robust screening cascade, with a focus on the hit-to-lead phase, followed by insights into how screening cascades evolve during the lead optimisation phase.