Chemical modulation of transcription factors

Wiedemann, Bianca; Weisner, Jörn; Rauh, Daniel

doi:10.1039/c8md00273h

Cited by 11 publications

(5 citation statements)

References 218 publications

(267 reference statements)

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“…Indeed, only preclinical evidence has been published thus far, confirming the ability of these compounds of modulating CREB preferentially [138]. Concerning the AKT pathway, even though several clinical trials are testing the efficacy of different AKT modulators, such as MK-2206, GDC-0068 and AZD5363, their effects on CREB-mediated transcriptional activity remain unclear [139]. Conversely, emerging evidence recently emphasizes how some tyrosine kinase inhibitors (TKIs), such as lapatinib and sorafenib, exert both antiproliferative and proapoptotic properties directly impacting on CREB activation [109,110,140,141].…”

Section: Creb-related Pathways Inhibitorsmentioning

confidence: 99%

Targeting CREB in Cancer Therapy: A Key Candidate or One of Many? An Update

Sapio

Salzillo

Ragone

et al. 2020

Cancers

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Intratumor heterogeneity (ITH) is considered the major disorienting factor in cancer treatment. As a result of stochastic genetic and epigenetic alterations, the appearance of a branched evolutionary shape confers tumor plasticity, causing relapse and unfavorable clinical prognosis. The growing evidence in cancer discovery presents to us “the great paradox” consisting of countless potential targets constantly discovered and a small number of candidates being effective in human patients. Among these, cyclic-AMP response element-binding protein (CREB) has been proposed as proto-oncogene supporting tumor initiation, progression and metastasis. Overexpression and hyperactivation of CREB are frequently observed in cancer, whereas genetic and pharmacological CREB downregulation affects proliferation and apoptosis. Notably, the present review is designed to investigate the feasibility of targeting CREB in cancer therapy. In particular, starting with the latest CREB evidence in cancer pathophysiology, we evaluate the advancement state of CREB inhibitor design, including the histone lysine demethylases JMJD3/UTX inhibitor GSKJ4 that we newly identified as a promising CREB modulator in leukemia cells. Moreover, an accurate analysis of strengths and weaknesses is also conducted to figure out whether CREB can actually represent a therapeutic candidate or just one of the innumerable preclinical cancer targets.

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Section: Creb-related Pathways Inhibitorsmentioning

confidence: 99%

Targeting CREB in Cancer Therapy: A Key Candidate or One of Many? An Update

Sapio

Salzillo

Ragone

et al. 2020

Cancers

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“…Transcription factors represent an important class of particularly challenging protein targets as they are often embedded in complex regulatory PPI networks and lack defined binding pockets that would be suitable for small molecule targeting 12 . A prime example are the members of the transcriptional enhanced associate domain (TEAD) family which are downstream effectors of the Hippo signalling pathway and crucially involved in tissue homeostasis, cell proliferation, and organ growth control, such as in the heart 13 .…”

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confidence: 99%

A protein tertiary structure mimetic modulator of the Hippo signalling pathway

et al. 2020

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Transcription factors are key protein effectors in the regulation of gene transcription, and in many cases their activity is regulated via a complex network of protein–protein interactions (PPI). The chemical modulation of transcription factor activity is a long-standing goal in drug discovery but hampered by the difficulties associated with the targeting of PPIs, in particular when extended and flat protein interfaces are involved. Peptidomimetics have been applied to inhibit PPIs, however with variable success, as for certain interfaces the mimicry of a single secondary structure element is insufficient to obtain high binding affinities. Here, we describe the design and characterization of a stabilized protein tertiary structure that acts as an inhibitor of the interaction between the transcription factor TEAD and its co-repressor VGL4, both playing a central role in the Hippo signalling pathway. Modification of the inhibitor with a cell-penetrating entity yielded a cell-permeable proteomimetic that activates cell proliferation via regulation of the Hippo pathway, highlighting the potential of protein tertiary structure mimetics as an emerging class of PPI modulators.

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“…TFs are the final players of signal transduction cascades, which often begin with extracellular ligand-binding events, followed by signal integration and processing, ultimately resulting in the initiation or repression of target gene transcription. [35] MiRNAs and TFs combine together in a functional network to alter gene expression in cancer. [36]…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-related transcription factor regulatory networks in human colorectal cancer

Hao¹,

Huo²,

Du³

et al. 2019

Medicine

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Objective Colorectal cancer (CRC) is an extremely common gastrointestinal malignancy. The present study aimed to identify microRNAs (miRNAs) and transcription factors (TFs) associated with tumor development. Methods Three miRNA profile datasets were integrated and analyzed to elucidate the potential key candidate miRNAs in CRC. The starBase database was used to identify the potential targets of common differentially expressed miRNAs (DEMs). Transcriptional Regulatory Element Database and Transcriptional Regulatory Relationships Unraveled by Sentence-based Text databases were used to identify cancer-related TFs and the TF-regulated target genes. Functional and pathway enrichment analyses were performed using the Database for Annotation, Visualization and Integration Discovery (DAVID) database, and the miRNA–TF–gene networks were constructed by Cytoscape. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression of genes and miRNAs. Results In total, 14 DEMs were found in CRC. By bioinformatics analysis, 5 DEMs (miR-145, miR-497, miR-30a, miR-31, and miR-20a) and 8 TFs (ELK4 (ETS-family transcription factor), myeloblastosis proto-oncogene like (MYBL)1, MYBL2, CEBPA, PPARA, PPARD, PPARG, and endothelial PAS domain protein (EPAS1)) appeared to be associated with CRC and were therefore used to construct miRNA–TF–gene networks. From the networks, we found that miR-20a might play the most important role as an miRNA in the networks. By qRT-PCR, we demonstrated that miR-20a was significantly upregulated in CRC tissues. We also performed qRT-PCR to identify the expression of miR-20a-related TFs (PPARA, PPARD, PPARG, EPAS1). Three of them, PPARA, PPARG, and EPAS1, were downregulated in CRC tissues, with statistically significant differences, while the downregulation of PPARD in CRC tissues was not significantly different. Pathway enrichment analyses indicated that the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway was the most significantly enriched pathway. Two main elements of the PI3K-Akt signaling pathway, phosphatase and tensin homolog deleted on chromosome 10 and B-cell lymphoma 2-associated agonist of cell death, were demonstrated to be downregulated in CRC. Conclusion The present study identified hub miRNAs and miRNA-related TF regulatory networks in CRC, which might be potential targets for the diagnosis and treatment of CRC.

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Chemical modulation of transcription factors

Cited by 11 publications

References 218 publications

Targeting CREB in Cancer Therapy: A Key Candidate or One of Many? An Update

Targeting CREB in Cancer Therapy: A Key Candidate or One of Many? An Update

A protein tertiary structure mimetic modulator of the Hippo signalling pathway

MicroRNA-related transcription factor regulatory networks in human colorectal cancer

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