STAT3 Signaling in Cancer: Small Molecule Intervention as Therapy?

McMurray, John S.; Klostergaard, Jim

doi:10.1016/b978-0-12-803963-2.50007-7

Cited by 3 publications

(3 citation statements)

References 174 publications

(150 reference statements)

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“…The goal of this section is to give an overview about how structural biology influenced the discovery of new biologically active molecules. The medicinal chemistry efforts to discover STAT3 inhibitors have been extensively reviewed elsewhere [ 9 , 11 , 63 , 64 , 65 , 66 ]. Here, therefore, we will discuss only selected examples of ligand-based drug design and how computational, structural and biochemical techniques have been used to understand the binding mode of STAT3 inhibitors.…”

Section: Drug Designmentioning

confidence: 99%

Structural Biology of STAT3 and Its Implications for Anticancer Therapies Development

Sgrignani

Garofalo

Matkovic

et al. 2018

IJMS

112

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Transcription factors are proteins able to bind DNA and induce the transcription of specific genes. Consequently, they play a pivotal role in multiple cellular pathways and are frequently over-expressed or dysregulated in cancer. Here, we will focus on a specific “signal transducer and activator of transcription” (STAT3) factor that is involved in several pathologies, including cancer. For long time, the mechanism by which STAT3 exerts its cellular functions has been summarized by a three steps process: (1) Protein phosphorylation by specific kinases, (2) dimerization promoted by phosphorylation, (3) activation of gene expression by the phosphorylated dimer. Consequently, most of the inhibitors reported in literature aimed at blocking phosphorylation and dimerization. However, recent observations reopened the debate and the entire functional mechanism has been revisited stimulating the scientific community to pursue new inhibition strategies. In particular, the dimerization of the unphosphorylated species has been experimentally demonstrated and specific roles proposed also for these dimers. Despite difficulties in the expression and purification of the full length STAT3, structural biology investigations allowed the determination of atomistic structures of STAT3 dimers and several protein domains. Starting from this information, computational methods have been used both to improve the understanding of the STAT3 functional mechanism and to design new inhibitors to be used as anticancer drugs. In this review, we will focus on the contribution of structural biology to understand the roles of STAT3, to design new inhibitors and to suggest new strategies of pharmacological intervention.

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Section: Drug Designmentioning

confidence: 99%

Structural Biology of STAT3 and Its Implications for Anticancer Therapies Development

Sgrignani

Garofalo

Matkovic

et al. 2018

IJMS

112

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“…AlphaScreen is an in vitro competitive binding test used to identify compounds that are able to inhibit the binding of proteins containing an SH2 domain to their corresponding phosphopeptides (5-carboxyfluorescein (FITC)-GpYLPQTV for STAT3 and FITC-GpYDKPHVL for STAT1) ( Table 2). Compounds characterized by an interesting STAT3 affinity were further investigated for their selectivity versus STAT1, which shows a high degree of sequence similarity to STAT3 but an opposite physiological role [24,25], and Grb2, as a model for other SH2 domain-containing proteins.…”

Section: Biological Evaluationmentioning

confidence: 99%

Towards the Inhibition of Protein–Protein Interactions (PPIs) in STAT3: Insights into a New Class of Benzothiadiazole Derivatives

et al. 2020

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Signal transducer and activator of transcription 3 (STAT3) is a validated anticancer target due to the relationship between its constitutive activation and malignant tumors. Through a virtual screening approach on the STAT3-SH2 domain, 5,6-dimethyl-1H,3H-2,1,3-benzothiadiazole-2,2-dioxide (1) was identified as a potential STAT3 inhibitor. Some benzothiadiazole derivatives were synthesized by employing a versatile methodology, and they were tested by an AlphaScreen-based assay. Among them, benzosulfamide 1 showed a significant activity with an IC50 = 15.8 ± 0.6 µM as a direct STAT3 inhibitor. Notably, we discovered that compound 1 was also able to interact with cysteine residues located around the SH2 domain. By applying mass spectrometry, liquid chromatography, NMR, and UV spectroscopy, an in-depth investigation was carried out, shedding light on its intriguing and unexpected mechanism of interaction.

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“…Compounds characterized by an interesting affinity were also investigated for their selectivity versus STAT1 having a high degree of sequence homology to STAT3 (78%) but an opposite physiological role. [46,47] Ligands 1 and 2 . HCl did not disrupt STAT3 dimerization whereas their corresponding Pt(II)…”

Section: 4mentioning

confidence: 99%

An in vivo active 1,2,5-oxadiazole Pt(II) complex: A promising anticancer agent endowed with STAT3 inhibitory properties

Porta

Facchetti

Ferri

et al. 2017

European Journal of Medicinal Chemistry

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STAT3 Signaling in Cancer: Small Molecule Intervention as Therapy?

Cited by 3 publications

References 174 publications

Structural Biology of STAT3 and Its Implications for Anticancer Therapies Development

Structural Biology of STAT3 and Its Implications for Anticancer Therapies Development

Towards the Inhibition of Protein–Protein Interactions (PPIs) in STAT3: Insights into a New Class of Benzothiadiazole Derivatives

An in vivo active 1,2,5-oxadiazole Pt(II) complex: A promising anticancer agent endowed with STAT3 inhibitory properties

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