The interaction between a target and its modulator can happen in a variety of ways, all of them resulting in the variation of the target activity at steady state. Although the final result could be identical, the way it is achieved is of extreme relevance for the therapeutic use of potential modulators. As an example, ATP competitive kinase inhibitors might be active on all kinases (and other proteins) with a homologous ATP binding domain.
The study of the mode of action (MoA) of a lead compound or drug candidate is typically carried out early on in the process of selecting a lead series. We use this information to prioritize series in hit-to-lead efforts or to drive the hit discovery process when one single mode of action is desired. To achieve this result, we apply biochemical techniques as well as biophysical orthogonal readouts.
MoA selective assay design
The primary biochemical assay used for hit identification can be designed in a way to facilitate the identification of modulators with a desired MoA. We typically achieve this by using high/low reagent concentrations in order to make the binding competition easier or harder.
The renaissance of covalent inhibitors
Despite being marginalized for years, covalent inhibitors are seeing a new resurgence. In fact, specific covalent inhibitors, when paired with a therapeutically meaningful target half-life, could result in very potent drugs with relatively low levels of side effects. We understand the importance of the time factor in studying covalent inhibitors, and we have long-standing experience in techniques such as jump-dilutions to confirm this mode of action.
MoAs determined to be activity based must be confirmed by orthogonal readouts. Our team has successfully used a variety of biophysical techniques such as SPR, LC-MS and NMR. In addition, our computational chemistry department greatly facilitates the interpretation of structural biology data and can help modelling the observed molecular interaction.
It is now clear that modern drug discovery cannot be carried out without taking into account binding kinetics. A long residence time (which we determine via SPR) is typically desirable for molecules without known mechanism-dependent toxicity. Nonetheless, kinetics data alone are not enough if not taken together with protein binding and compound clearance. Through the interplay between biology and pharmacology, our team can align all this parameters in the fastest way possible.
The success of a therapeutically relevant compound must be prepared in advance, considering all possible options and designing the tools to interrogate the biology in the smartest way. We have created a suite of tools and expertise to prioritize the most meaningful mode of action for a defined therapeutic intervention.