Given the role of transcriptional misregulation in the pathogenesis of human disease, there is enormous interest in the development of molecules that exogenously control transcription in a defined manner. The past decade has seen many exciting advancements in the identification of molecules that mimic or inhibit the interactions between natural transcriptional activators and their binding partners. In this minireview, we focus on four activator⅐target protein complexes, highlighting recent advances as well as challenges in the field.Just as specific transcriptional patterns signify the differentiation of stem cells into individual tissues, unique transcriptional signatures are associated with every human disease either as a cause or as an effect. For example, Ͼ50% of human cancers exhibit loss-of-function mutations in the tumor suppressor and transcriptional activator p53 (1, 2). There is thus enormous interest in identifying exogenous agents that one can use to influence transcriptional events in a predefined manner. One attractive strategy is the design or discovery of molecules that reconstitute the function of a natural transcription factor that can then be used to directly impact the transcriptional state of predefined genes. A second, related approach is to identify molecules that mimic one aspect of the structure of a particular transcription factor and in doing so serve as competitive inhibitors of important binding interactions. For both of these strategies, transcriptional activators of the amphipathic class have served as the inspiration, and molecules that reconstitute one or more of the functions of these complex transcription factors have been outstanding mechanistic tools with considerable therapeutic promise. As a visible and rapidly evolving field, progress in this area is frequently reviewed (3-8). In this minireview, we focus on four examples of activator⅐target protein complexes to highlight recent successes as well as the significant challenges remaining in the field.
Small molecules that mimic the transcriptional activation domain of eukaryotic transcriptional activators have the potential to serve as effective inhibitors of transcriptional processes. Here we show that one class of transcriptional activation domain mimics, amphipathic isoxazolidines, can be converted into inhibitors of gene expression mediated by the transcriptional activator ESX through small structural modifications. Addition of the small molecules leads to decreased expression of the cell surface growth receptor ErbB2(Her2) in ErbB2-positive cancer cells and, correspondingly, decreased proliferation.
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