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Understanding the dynamics of target engagement to maximize the probability of program success

One of the reasons for the high attrition rate in drug discovery, beyond toxicity, is the failure to meet efficacy endpoints in Phase Two clinical trials.

After several years of retrospective analysis, scientists working in the drug discovery field have reached the conclusion that the clinical efficacy pitfall can be mitigated by better  pre-clinical models.

Target engagement is the key in vitro/in vivo tool that can dramatically improve the probability of success for a lead compound, to move forward in the drug discovery pipeline. Efficacy readout alone can be easily confounded by a number of uncontrolled events. However, target engagement readout offers several benefits:

  • It reports on the activity on the primary target so is devoid of too many off-targets events
  • It is best suited for structure-activity relationship (SAR) studies in cells
  • It is a fast readout, thus enabling higher productivity discovery cycles
  • It can be often adapted to become a pharmacodynamic readout for in vivo studies

We evaluate the development of a suite of biological assays and tools, even at very early drug discovery stages, in order to make sure we work primarily on targets and compounds with a high probability of success. We know that every single target might have its own assay requirements and we want to be prepared for the majority of scenarios. Therefore, we developed and optimized various technologies for target engagement assays.

Among the most successful strategies and technologies that we use are:

  • Luciferase fusion stability assay
  • Nano-BRET
  • In-cell target activity readouts (i.e. secondary messengers, substrate/product quantification, imaging, etc.)
  • Target stabilization/destabilization (thermal-shift, HSPs destabilization)
  • Target protein half-life (radiometric)
  • Immunoassays (e.g. ELISA, MSD, SMC, etc.) for target and/or pathway events detection.

Target engagement is a must-have in modern drug discovery and we are strong supporters of these types of assays. Our team has extensive experience on how to match different technologies to the specifications of the target/biological system under investigation.

Target engagement assays, together with later functional/phenotypic readouts, represent the cornerstone of every drug discovery program and are shown to enable informed strategic decisions to speed up the discovery of new drug candidates.

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