Solution-Phase Combinatorial Libraries: Modulating Cellular Signaling by Targeting Protein-Protein or Protein-DNA Interactions

The high‐throughput synthesis and screening of compound libraries hold tremendous promise for drug discovery and powerful methods for both solid‐phase and solution‐phase library preparation have been introduced. The question of which approach (solution‐phase versus solid‐phase) is best for the preparation of chemical libraries has been replaced by which approach is most appropriate for a particular target or screen. Herein we highlight distinctions in the two approaches that might serve as useful considerations at the onset of new programs. This is followed by a more personal account of our own focus on solution‐phase techniques for the preparation of libraries designed to modulate cellular signaling by targeting protein–protein or protein–DNA interactions. The screening of our libraries against a prototypical set of extracellular and intracellular targets, using a wide range of assay formats, provided the first small‐molecule modulators of the protein–protein interactions studied, and a generalized approach for conducting such studies. To bead or not to bead? This is the question posed at the start of the construction of every combinatorial library. The pros and cons of solid‐phase and solution‐phase library synthesis are discussed along with the authors personal experiences in constructing and using solution‐phase libraries (see scheme) to study the modulation of protein–protein and protein–DNA interactions in cellular signal transduction.