Objective

The availability of kinetic information of compounds in early phases of drug discovery is useful in driving the Med. Chem. strategy. The challenge in earlier phases of a drug discovery is that there are compounds from multiple series requiring the profiling of large numbers of compounds. In contrast, detailed mechanistic characterisation of compounds is usually very low throughput, often due to the limited capacity of automation.

The FLIPR Tetra System enables liquid sample transfer and is equipped with a CCD camera that simultaneously detects fluorescence from all wells. The system is well established for cell assays but was never explored for biochemical mechanistic assays. Using Tyrosine Kinase as a model system, we have delivered a novel platform combining FLIPR Tetra with Assay Quant technology allowing fifteen-fold increase in throughput from 28 compounds to 420 compounds per day. The system can generate mechanistic data including On rate constant( kon), Off rate constant ( koff) and Inactivation rate constant( kinact).The capacity is compatible with structure-kinetic relationship based progress during LIID and LOID stage, facilitating mechanistically driven medicinal chemistry along with traditional structure-activity relationship based approach.