× Medicines Discovery Catapult

Lack of efficacy is the greatest cause of drug discovery failure during clinical trials. Demonstrating proof-of-mechanism – evidence that a lead molecule engages with its molecular target and affects the biology of the target cell as intended – can significantly reduce this element of project attrition.

Target Engagement describes the measurement of interaction between a lead molecule and its protein target, together with analysis of the kinetics and mechanism of this interaction.

Target Validation links this compound-target interaction to biological effect in a translatable system and builds confidence in the target hypothesis.

We are looking for collaborations with:

  • Partners that have a lead molecule, and a requirement to build a data-package around target engagement, target validation or compound mechanism-of-action.
  • Academics or companies with a novel technology that can be applied to measure direct compound-target engagement in cells or using purified protein.
  • Academics or companies with in vitro delivery technologies that could be used to deliver molecular tools into primary and iPS-derived cells.
  • Academics or companies with novel methods for target validation or target deconvolution.

Our team are establishing a target engagement & validation platform based around three questions:

  1. Does my lead molecule reach its desired site of action?
  2. Does my compound engage with its protein target and what are the characteristic of this interaction?
  3. What are the downstream consequences of drug-target interaction and how do they link to the biological hypothesis?

By focussing our work on translatable cell models and on technologies that are not widely available, we aim to build a unique platform for collaborative R&D.

Our aims through collaborative R&D

  • Apply mass spectrometry and pre-clinical imaging to measure drug distribution and intracellular compound concentration
  • Establish a suite of cellular target engagement methods and, where possible, apply them to primary and iPS-derived cells.
  • Identify, develop and provide access to biochemical (purified protein) assay technologies that are not widely available for medicines discovery
  • Establish high-content read-outs of biological response and apply to target validation studies in combination with molecular approaches to provide target knock-down.

Our work in target engagement & validation will allow SMEs to:

  • Demonstrate target engagement for their lead molecules in translatable cell systems
  • Characterise the binding, kinetics and mechanism-of-action of their lead molecules
  • Test their novel target engagement & validation technologies in complex cell models, using cutting-edge technologies to generate high value data-sets.
  • Build target validation data packages through the application of data-rich assay readouts

Our technologies

  • VIAFLO contact liquid handling
  • Plate based multi-drop dispensers
  • Automated cell assay system (High Res arm)
  • ClarioSTAR and HiDex microplate readers
  • Bluecat, Biotek and Berthold plate washer