Drug discovery is always evolving. From new processes to advanced technologies, excellence in drug discovery is the result of combining different approaches. And each approach brings a specific answer.
Successful researchers and companies master and use different technologies, making sure the interpretation of data does not suffer experimental or analytical bias and leads to better success rates and higher profitability for drug developers.
Emerging and Resurrecting Technologies
We’ve made huge strides in the drug discovery process, and it’s only getting better as we move forward.
Here are two predictions for the future:
Alpha CETSA® for target engagement
While traditional assay methods detect either the displacement of a radioligand binding to the target by a competitor molecule, or the modulation of some function of the target, a new method is making headway: Cellular Thermo Shift Assay (CETSA) from Pelago Bioscience.
CETSA relies on the ability of small molecules to stabilize their target protein with regards to their thermal denaturation in the context of a physiologically relevant and pathology pertinent cellular environment.
In this assay, cells are incubated with the compound and heated. By heating at different temperatures, a target melting curve is measured. Using reference compounds, a certain temperature point is identified where the compound-stabilized protein target stays in supernatant whereas noncompound stabilized proteins aggregates/precipitates. This can be detected using various technologies, like western blotting, AlphaLISA immunoassay, or mass spectrometry. Such methods demonstrate that new compounds under development are able to bind their target protein (target engagement).
CETSA are useful tools in confirming target engagement, giving scientists confidence to proceed with their compound. In addition, as this method does not rely on competition versus a specific binding site or on the recording of a specific function of the target protein, it has a promising potential to lead to the discovery of innovative new families of compounds, modulating the target via the binding to novel, yet unexplored, regions of the target protein.
As no target overexpression or fusion with any reporter protein is needed to run a CETSA, this method allows for the generation of target engagement data in stable cell lines, and more importantly, in more physiologically relevant primary cells or in vivo cells (using tissues from animal models treated with the drug). As such, this assay allows for the collection of very relevant data being better predictive of what the efficacy of the compound will be in the clinics.
Scintillation proximity assay for residence time
Scintillation proximity assays (SPAs) provide a sensitive, no-wash platform used for a wide range of biological interactions including drug-target binding affinity studies. SPAs allow for the collection of information such as residence time in a platform that is well suited for radiometric high-throughput screening.
Compound-target residence time is a critical and previously neglected component of molecular activity and the indicator of drug efficacy. There has been a resurgence of interest in the development of small molecules modulating kinases and of antibodies to cell surface receptors, guided by the selection of molecules having the longest residence time, as this is a key factor to the specificity and real efficacy of new therapeutics. By assessing residence time, failure further down the drug discovery workflow can be avoided.
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to learn more about cell-based assays and what to consider as you design yours.