Objective

It has been our experience that the primary gains in potency as a series progresses have largely been due to increased residence time. We have exploited this fundamental feature and the concept of group efficiency to assess crude unpurified reactions to identify the target molecules with significant improvements in koff. Here we will demonstrate that these same crude reactions can be used to determine a full thermodynamic and kinetic signature, including KA, from a single ITC thermogram. Additionally, we will present data that demonstrates that these unpurified reactions can be exploited in a number ways important for drug discovery, structure, stability and cellular properties. This achieves several aims; improving hits-to-lead turn-around times, significant saving in material costs, “greener” chemistry, and permits more hit series to be exploited for the same resource. We will demonstrate the utility of this approach with examples from HSP90, PIN1 and PDK1/2 and a currently un-drugged target.