Workpackage 2: Getting up to speed with drug-target kinetics: Development of robust off-the-shelf assays

During lead development, the pharmaceutical industry has heavily relied on high-throughput assays in order to find possible drug candidates for the many diseases that we face as society. For various reasons, focus of these assays has been on two main drug characteristics: affinity for its disease target and its ability to selectively modulate signaling. In contrast drug-target kinetics, which we believe has an important added value in drug discovery and optimization, has lacked the necessary assays with enough throughput and robustness, preventing an optimal integration of drug-target kinetics analysis in the drug discovery and development process. Moreover, variability in assay conditions and techniques make it difficult to compare drug target kinetics between experiments.

"K4DD combines both the expertise on drug targets as well as technologies to achieve robust assays for kinetic binding rates"

By addressing the throughput and accuracy in determining drug-target kinetics, it will be possible to make smarter decisions earlier in the drug discovery phase leading to less attrition later in development. Within WP2 leading academic and industry research groups in the field of drug-target assay techniques, have joined forces to both compare and standardize the necessary assays to screen the interaction of potential drug candidates with a number of selected targets. With combined effort, the consortium's ultimate goal is to establish a set of experimental blueprints that is adaptable to virtually any drug-target system. Futhermore by gathering the drug-target kinetics for assay optimization, WP2 will also support other efforts of the consortium revolving around molecular understanding and in vivo implications of a drug kinetic signature.

Optimization of techniques by increasing the throughput [D.Guo, 2012], adapting techniques to difficult (e.g. instable) protein targets [I. Navratilova, 2005] and measuring kinetics in more physiological relevant systems [S.J. Briddon, 2004] is already ongoing. New efforts, by the consortium and other experts, include improving throughput with various techniques like Surface Plasmon Resonance (SPR), but also side-by-side comparison of techniques adapted to the same drug target. For instance the conceptually interesting Histamine 1 receptor (H1R) has been successfully employed as a drug target to reduce inflammation. Since this protein is normally expressed on the membrane, stability can be an issue in techniques that rely on purification of the protein. Multiple techniques are now adapted to this receptor and knowhow will be distributed and compared side by side within the consortium. This ultimately should be the basis of developing a robust and time efficient off-the-shelf assay.

WP2 at a glance:

  • 6 universities
  • 6 big pharmaceutical companies
  • 2 small and medium sized enterprises

Challenges: 

  • Drug-target stability
  • Drug-target adaptability
  • Assay throughput
  • Assay comparison

Techniques:

  • Surface Plasmon Resonance
  • Fluorescence Correlation Spectroscopy
  • Attenuated total reflectance - Fourier-transformed Infra Red
  • Impedence based Label-free techniques
  • Isothermal Titration
  • Calorimetryradioligand binding

Workpackage leaders:

  • Prof. A. Hopkins PhD (Andrew)
  • A. Ruf PhD (Armin)

 

 

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