Amphipathic Small Molecules Mimic the Binding Mode and Function of Endogenous Transcription Factors
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 signiﬁcant, however. Many protein–protein interactions require multiple points of contact over relatively large surface areas. More signiﬁcantly, 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 proﬁle in order to stimulate gene expression. Here we describe a unique class of small molecules that exhibit both function and a binding proﬁle analogous to natural transcriptional activation domains. Of particular note, the small molecules are the ﬁrst 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.
Brennan, Brian; Buhrlage, Sara; Bates, Caleb; Rowe, Steven; Minter, Aaron; Majmudar, Chinmay; Wemmer, David; Al-Hashimi, Hashim; and Map, Anna, "Amphipathic Small Molecules Mimic the Binding Mode and Function of Endogenous Transcription Factors" (2009). Scholarship. 4.