Ulf Bömer

High‐Throughput Screening for Kinase Inhibitors

Following G protein‐coupled receptors (GPCRs), protein kinases have become the second most important class of targets for drug discovery over the last 20 years. While only four kinase inhibitors have reached the market to date (Fasudil for rho‐dependent kinase, Rapamycin for TOR, Gleevec for BCR‐Abl, and Iressa for EGFR), many more are already in clinical development. A historical overview of kinase inhibitors was recently published by Cohen. 1 After the previous successes, protein kinases are now regarded as attractive, well‐drugable targets, and the analysis of the human genome has yielded 518 protein kinases. 2 We can thus expect screening for protein kinase inhibitors to become even more important in the future. In this review we will focus on the early steps of drug discovery programs producing new lead compounds. We will guide the reader through efficient state‐of‐the‐art assay development and high‐throughput screening of large chemical libraries for protein kinase inhibitors.

A Cost-Effective Solution to Reduce Dead Volume of a Standard Dispenser System by a Factor of 5

A key trend in high-throughput screening is assay miniaturization to control reagent costs and increase throughput. For this purpose, liquid-handling devices are used that transfer nano-to low-microliter volumes into all currently used microtiter well plates. One drawback of many available dispenser and pipetting systems are high dead volumes. Therefore, the authors were looking for an easy and simple solution to modify their standard liquid-handling device, PerkinElmer’s FlexDrop™ Precision IV, allowing for a dead volume reduction to receive maximum benefit from miniaturized assay formats. Internal reservoirs were developed and constructed by Schering’s Technical Development Laboratory (TDL), which are directly connected to the dispenser banks of FlexDrop™ without tubing. Using these newly built reservoirs, the dead volume was decreased by a factor of 5 in comparison to the manufacturer’s reservoirs without compromising liquid-handling parameters such as accuracy and precision. The modified system displayed a high robustness and reliability under routine high-throughput screening conditions.