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question of which approach (solution-phase versus solid-phase) is best for the preparation of chemical libraries has been replaced by which approach is most appropriate for a particular target or screen.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.

The erythropoietin receptor (EPOr) is activated by ligand-induced homodimerization, which leads to the proliferation and differentiation of erythroid progenitors. Through the screening of combinatorial libraries of dimeric iminodiacetic acid diamides, novel small molecule binders of EPOr were identified in a protein binding assay. Evaluation of a series of analogues led to optimization of binding subunits, and these were utilized in the synthesis of higher order dimer, trimer, and tetramer libraries. Several of the most active EPOr binders were found to be partial agonists and induced concentration-dependent proliferation of an EPO-dependent cell line (UT-7/EPO) while having no effect on a cell line lacking the EPOr (FDC-P1). An additional compound library, based on a symmetrical isoindoline-5,6-dicarboxylic acid template and including the optimized binding subunits, was synthesized and screened leading to the identification of additional EPO mimetics.

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Hochdurchsatzsynthese und ‐screening von Verbindungsbibliotheken haben große Erwartungen für die Wirkstoffsuche geweckt. Für die Herstellung solcher Bibliotheken an der Festphase und in Lösung sind leistungsfähige Methoden entwickelt worden. Die Synthesestrategie wird schon lange nicht mehr nach allgemeinen Erwägungen ausgewählt, sondern mit Blick auf die spezielle Fragestellung. In diesem Aufsatz beschreiben wir Unterschiede zwischen den beiden Methoden, die bei der Entwicklung neuer Programme helfen sollen. Als Beispiel beschreiben wir unsere Versuche, mithilfe von Lösungstechniken Modulatoren für zelluläre Signale durch Beeinflussung von Protein‐Protein‐ oder Protein‐DNA‐Wechselwirkungen zu identifizieren. Das Vorurteil, niedermolekulare Substanzen seien für therapeutische Intervention an solchen Zielstrukturen ungeeignet, konnten wir beim Screening unserer Bibliotheken gegen eine repräsentative Auswahl extrazellulärer und intrazellulärer Targets widerlegen: Mithilfe zahlreicher Testmethoden identifizierten wir die ersten niedermolekularen Modulatoren für Protein‐Protein‐Wechselwirkungen und erarbeiteten ein allgemeines Verfahren für derartige Untersuchungen.

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