Expanding the repertoire of small molecule transcriptional activation domains

Casey, Ryan J.; Desaulniers, Jean-Paul; Højfeldt, Jonas W.; Mapp, Anna K.

doi:10.1016/j.bmc.2008.02.045

Cited by 11 publications

(12 citation statements)

References 28 publications

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“…(43, 45) Med23(352-625) and Med15(1-357) were bacterially expressed and purified as previously described. (52, 77) Fluorescence polarization binding experiments were conducted as previously reported.…”

Section: Methodsmentioning

confidence: 99%

“…b) Isoxazolidine TADs (iTADs) that were designed to generically mimic their natural counterparts and up-regulate transcription when localized to a specific promoter (when R = DBD). (42-45)…”

Section: Figuresmentioning

confidence: 99%

“…(42) (43) This molecule and related iTADs ( 2, 3 ) were designed to emulate amphipathic TADs, with hydrophobic and polar functional groups displayed on a conformationally constrained scaffold similar to a helix. (44, 45) However, an open question was if these small molecules were genuine TAD mimics, able to replicate the complex binding pattern(s) of their endogenous counterparts in addition to up-regulating transcription. Here a detailed study of the interaction with one binding partner, the kinase-inducible (KIX) domain of the histone acetyltransferase Creb binding protein (CBP)(15, 16, 46), reveals that the binding footprint of the iTADs and the binding-induced changes in CBP are remarkably similar to that of the endogenous TADs that target this site, including that of MLL (mixed lineage leukemia factor).…”

mentioning

confidence: 99%

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

Buhrlage¹,

Bates²,

Rowe³

et al. 2009

ACS Chem. Biol.

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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 pre-programmed for such multi-modal binding. This is the case for the transcriptional activation domain or TAD of transcriptional activators as these mofifs utilize a poorly characterized multi-partner 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 non-functional 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.Transcriptional activators are essential for high fidelity transcription, responsible for seeking out particular genes and up-regulating them to precise levels in a signal-responsive fashion.(1,2) Indeed, the altered transcription patterns observed in disease states can often be attributed to malfunctioning and/or mis-regulated transcriptional activators.(3-6) Alterations in the function of the tumor suppressor p53, for example, are found in >50% of all human cancers; (7,8) similarly, constitutively active NF-κB, an activator that regulates genes responsible for apoptosis, inflammatory response, and proliferation, is observed in inflammatory disorders and most cancers.(9,10) There is thus tremendous interest in the development of activator artificial transcription factors (activator ATFs), nonnatural molecules programmed to perform the same function as endogenous activators, as both mechanistic tools and as transcription-targeted therapeutic agents. (2,(11)(12)(13)(14) The architecture of activator ATFs is analogous to that of their natural counterparts in that they minimally consist of a DNA binding domain (DBD) that confers gene-targeting specificity and a transcriptional activation domain (TAD) that controls *Corresponding author, amapp@umich.edu.. The challenges associated with small molecule TAD discovery are due in large part to the scarcity of molecular-level details regarding natural TAD function. The largest and most well studied class of activators is the amphipathic class, characterized by interspersed polar a...

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Section: Methodsmentioning

confidence: 99%

Section: Figuresmentioning

confidence: 99%

mentioning

confidence: 99%

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

Buhrlage¹,

Bates²,

Rowe³

et al. 2009

ACS Chem. Biol.

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“…In addition, protein-protein interaction assays showed how AR-coactivator complexes can identify compounds that interfere with the receptor-coactivator interface and subsequently modulate the proliferation of prostate tumors. Anna Mapp (University of Michigan, Ann Arbor) described small molecules capable of acting as transcriptional switches that they used to study the activation factor 1 (amphipathic or N-terminal transcription domains) of NRs (15). These domains are difficult to characterize and may hold the key to understanding the complexity and diversity of transcriptional activities attributed to NRs.…”

Section: Development and Use Of New Toolsmentioning

confidence: 99%

Chemical Approaches to Nuclear Receptors in MetabolismA report on the workshop “Chemical Approaches to Nuclear Receptors and Metabolism,” sponsored by National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA, 16 to 17 April 2009.

Margolis¹,

Moore²,

Willson³

et al. 2009

Sci. Signal.

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The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsored a workshop, “Chemical Approaches to Nuclear Receptors and Metabolism,” in April 2009 to explore how chemical and molecular biology and physiology can be exploited to further our understanding of nuclear receptor structure, function, and role in disease. Signaling cascades involving nuclear receptors are more complex and interrelated than once thought. Nuclear receptors continue to be attractive targets for drug discovery. The overall goal of this workshop was to identify gaps in our understanding of the complexity of ligand activities and begin to address them by (i) increasing the collaboration of investigators from different disciplines, (ii) developing a better understanding of chemical modulation of nuclear receptor action, and (iii) identifying opportunities and roadblocks in the path of translating basic research to discovery of new therapeutics.

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“…Thus, in the absence of a DNA-targeting moiety, we reasoned that this molecule could serve as a competitive inhibitor of activator-coactivator interactions (Figure 1a). Supporting this idea, the isoxazolidine TADs display a multi-partner binding profile consistent with their natural counterparts; in addition, small structural changes alter the binding pattern of the TAD mimics 6, 12. We hypothesized that this molecular scaffold would be an excellent starting point for inhibitor development.…”

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confidence: 94%

Inhibition of ErbB2(Her2) expression with small molecule transcription factor mimics

Lee

Taylor

Desaulniers

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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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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Expanding the repertoire of small molecule transcriptional activation domains

Cited by 11 publications

References 28 publications

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

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

Chemical Approaches to Nuclear Receptors in MetabolismA report on the workshop “Chemical Approaches to Nuclear Receptors and Metabolism,” sponsored by National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA, 16 to 17 April 2009.

Inhibition of ErbB2(Her2) expression with small molecule transcription factor mimics

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