Residence time and kinetic efficiency analysis of extracellular signal-regulated kinase 2 inhibitors |
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Authors: | Darin Vanderpool Charles E Grimshaw J David Lawson Jacques Ermolieff |
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Institution: | 1. Enzymology and Biophysical Chemistry Group, Takeda California, San Diego, CA 92121, USA;2. Computational Sciences and Crystallography Group, Takeda California, San Diego, CA 92121, USA |
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Abstract: | The RAS/RAF/MEK/ERK signal transduction cascade plays an important role in the regulation of critical cellular processes such as cell proliferation, migration, and differentiation. The up-regulation of this pathway can negatively affect cell homeostasis and is responsible for the development of various forms of cancer and inflammation processes. Therefore, there is a strong interest in pursuing drug programs targeting some of the enzymes involved in this pathway. In addition to the determination of Ki, Kd, IC50, and/or EC50, a more thorough kinetic analysis can provide useful information for the selection of the best lead series during the early stage of the drug discovery process. This study describes a medium-throughput fluorescent probe displacement assay for the rapid determination of the koff constant, residence time, and kinetic efficiency for ERK (extracellular signal-regulated kinase) inhibitors. Using this method, we have identified several inhibitors that we have subjected to further kinetic analysis by comparing koff constants determined for these time-dependent inhibitors using either the active or inactive form of ERK2. |
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Keywords: | Structure&ndash kinetic relationship Kinetic efficiency ERK2 Time-dependent inhibition Off-rate Residence time |
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