Coactivator binding inhibitor

Dataset 2 is an ER-inhibitor dataset obtained from Pub-Chem (26). The dataset consists of 86,098 compounds tested on both ER-a (Bioassay 629 HTS of Estrogen Receptor-alpha Coactivator Binding inhibitors, Primary Screening) and ER-f) (Bioassay 633 HTS for Estrogen Receptor-beta Coactivator Binding inhibitors, Primary Screening). 

Two major issues have to be dealt with in the search for such types of coactivator binding inhibitors (CBIs) [9]. First of all it has to be proven whether direct inhibition of this interaction is a valid principle to antagonize nuclear receptor functioning. Apart from via the AF-2, nuclear receptors also control gene transcription via their activation function 1 (AF-1), located at the N-terminus of the protein, in a more or less ligand-independent way. This additional interaction actually results in more complex... 

Trialkylated 1,3,5-trithiane 277 has been evaluated as low inhibitor of strogen receptor a-coactivator binding (Scheme 70)450. 

Rodriguez AL, Tamrazi A, Collins ML, Katzenellenbogen JA. Design, synthesis, and in vitro biological evaluation of small molecule inhibitors of estrogen receptor alpha coactivator binding. I Med Chem 2004 47 600-11. 

In order for estrogen-mediated genomic activation to occur, the ligand-ER complex must bind to other nuclear proteins (coregulator proteins) that can either act as coactivators (stimulators of gene transcription) or corepressors (inhibitors of gene transcription) for access of the complex to the EREs (for... 

Common mediator Smads The mode of action of Smad 4 clearly differs from that of the other members of the Smad family. Smad 4 binds to phosphorylated pathway-restricted Smads and forms hetero-ohgomeric complexes. These translocate to the nucleus where they bind to related DNA elements and activate the transcription of target genes, e.g., the genes for the CDK inhibitors pl5 and p21 (see Chapter 13) (Fig. new). Activation of transcription often occurs in cooperation with other coactivators (see 1.4.3.2). 

The mechanism by which MTF-1 facilitates zinc-induction of metallothionein promoter through the MREs is not known, but several models have been proposed. First, zinc may act as a coinducer by binding to MTF-1 and creating an allosteric change, allowing MTF-1 to bind to the MREs. The model proposed for mammalian MTF-l/MRE interaction has already been proven for yeast copper metallothionein systems (Furst et al., 1988). Another possibility may be that, under normal conditions, an inhibitor binds MTF-1. When an influx of zinc occurs, MTF-1 binds the zinc, undergoes a conformational change and is released from the inhibitor. The protein would then have the ability to bind to the MREs. Finally, upon an increase in intracellular zinc concentration, a specific coactivator may bind zinc and interact with MTF-1 to maximally induce transcription. 

Mi LZ, et al. Structural basis for bile acid binding and activation of the nuclear receptor FXR. Mol. Cell 2003 11 1093-1100. Leduc AM, et al. Helix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactions. Proc. Natl. Acad. Sci. U.S.A. 2003 100 11273-11278. 

Figure 4 Inhibitors of activator-coactivator and activator-masking protein interactions. Structures of small molecules that compete effectively with transcriptional activators for binding sites within coactivators and within masking proteins.

Fig. 2.2 (c) Effects on NFkB. Binding ofVIP to VPACl initiates two transduction pathways, a cAMP-dependent and a cAMP-independent pathway. The cAMP-independent pathway inhibits IKK kinase, stabilizing the IkB inhibitor, and preventing p55 nuclear translocation. The cAM P-depen-dent pathway affects two separate transduction pathways 1) phosphorylation of CREB (CREB-P) which, due to its high affinity for the coactivator CBP, prevents CBP association with p55 and 2) inhibition of MEKKl phosphorylation, and of... 

Fig. 16.13. Steroid hormone receptors. A. Domains of the steroid hormone receptor. The transactivation domain (TAD) binds coactivators DNA-binding domain (DBD) binds to hormone response element in DNA ligand-binding domain (LBD) binds hormone NLS is the nuclear localization signal the dimerization sites are the portions of the protein involved in forming a dimer. The inhibitor binding site binds heat shock proteins and masks the nuclear localization signal. B. Transcriptional regulation by steroid hormone receptors. Additional abbreviations HSP, heat shock proteins GRE, glucocorticoid response element GIZ, glucocorticoid receptor.

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