Amphipathic Small Molecules Mimic the Binding Mode and Function of Endogenous Transcription Factors

<div class="line" id="line-19"> Small molecules that reconstitute the binding mode(s) of a protein and in doing so elicit a programmed functional response offer considerable advantages in the control of complex biological processes. The development challenges of such molecules are signi&filig;cant, however. Many protein&ndash;protein interactions require multiple points of contact over relatively large surface areas. More signi&filig;cantly, several binding modes can be superimposed upon a single sequence within a protein, and a true small molecule replacement must be preprogrammed for such multimodal binding. This is the case for the transcriptional activation domain or TAD of transcriptional activators as these motifs utilize a poorly characterized multipartner binding pro&filig;le in order to stimulate gene expression. Here we describe a unique class of small molecules that exhibit both function and a binding pro&filig;le analogous to natural transcriptional activation domains. Of particular note, the small molecules are the &filig;rst reported to bind to the KIX domain within the CREB binding protein (CBP) at a site that is utilized by natural activators. Further, a comparison of functional and nonfunctional small molecules indicates that an interaction with CBP is a key contributor to transcriptional activity. Taken together, the evidence suggests that the small molecule TADs mimic both the function and mechanism of their natural counterparts and thus present a framework for the broader development of small molecule transcriptional switches.</div>