A STAT inhibitor patent review: progress since 2011

Lai, Ping‐Shan; Rosa, David A.; Ali, Ahmed M.; Gómez‐Biagi, Rodolfo F.; Ball, Daniel P.; Shouksmith, Andrew E.; Gunning, Patrick T.

doi:10.1517/13543776.2015.1086749

Cited by 51 publications

(38 citation statements)

References 79 publications

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“…Thus, our data suggest that this short peptide may coordinate with IFNα, spatially regulating the signaling of the interferon in the cytokine cascade pathway. It would also be interesting to examine if the alteration of the signal pathway, using reagents as previously reported [38][39][40][41], will affect the therapeutic antitumor activity of the synthetic IFNP.…”

Section: Discussionmentioning

confidence: 99%

Targeting Jurkat T Lymphocyte Leukemia Cells by an Engineered Interferon-Alpha Hybrid Molecule

et al. 2017

Cell Physiol Biochem

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Background/Aims: Adult T-cell leukemia/lymphoma (ATL) is a very aggressive T cell malignancy that carries a poor prognosis, primarily due to its resistance to chemotherapy and to lifethreatening infectious complications. Interferon-alpha (IFNα) has been used in combination with the anti-retroviral drug zidovudine to treat patients with ATL. However, the efficacy of long-term therapy is significantly limited due to the systemic toxicity of IFNα. Methods: We utilized phage display library screening to identify short peptides that specifically bind to Jurkat T lymphocyte leukemia cells. By fusing the Jurkat-binding peptide to the C-terminus of IFNα, we constructed an engineered chimeric IFNα molecule (IFNP) for the treatment of ATL. Results: We found that IFNP exhibited significantly higher activity than wild type IFNα in inhibiting the growth of leukemia cells and inducing cell blockage at the G0/G1 phase. The synthetic IFNP molecule exerted its antitumor activity by upregulating the downstream genes involved in the STAT1 pathway and in apoptosis. Using a cell receptor binding assay, we showed that this Jurkat-binding peptide facilitated the binding affinity of IFNα to the cell surface type I IFN receptor. Conclusion: The isolated Jurkat-binding peptide significantly potentiates the therapeutic activity of IFNα in T lymphocyte leukemia cells. The engineered IFNP molecule may prove to a novel antitumor approach in the treatment of patients with ATL.

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Section: Discussionmentioning

confidence: 99%

Targeting Jurkat T Lymphocyte Leukemia Cells by an Engineered Interferon-Alpha Hybrid Molecule

et al. 2017

Cell Physiol Biochem

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“…10 As STAT3 (Signal Transducer and Activator of Transcription 3) occupies a noteworthy position in cancer biology, 11 we decided to explore the relevance of these chemical systems against this target. Among the recognized STAT3 direct inhibitors reported in the literature many are sulfur-containing compounds, such as sulfones (Stattic), 12 sulfonates (S31-201) 13 or sulfonamides (SF-1-066 and BP-1-102), 13 but no DTTs or MTSs have been so far considered. As we recently published our results on several oxadiazole derivatives able to interfere with the STAT3 signaling pathway, [14][15][16][17] we thought it of interest to link this heterocyclic scaffold to DTT and MTS moieties.…”

Section: Introductionmentioning

confidence: 99%

“…Compound 15 was prepared from 1H-imidazole-4-carbaldehyde, protected as N-methyl derivative by iodomethane 22 (13), then transformed into 14 through a selective palladium-catalyzed C-H activation in position 5. 23 The subsequent reduction step afforded the desired product 15 in good yield (Scheme 1b).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of new dithiolethione and methanethiosulfonate systems endowed with pharmaceutical interest

Gabriele¹,

Porta²,

Facchetti³

et al. 2016

Arkivoc

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Here we report synthetic methodology affording in the most efficient way the rapid preparation of new dithiolethiones (DTTs) and methanethiosulfonates (MTSs). These were evaluated as STAT3 inhibitors since these electrophilic systems could react with thiol groups of STAT3-SH2 domain. The results showed that MTSs strongly interacted with the SH2 domain, whereas the corresponding DTTs possessed lower affinity, independently from the nature of the linked heterocyclic scaffold.

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“…Malfunctions in this pathway are known to result in immune system disorder and cancers. Therefore, the JAK-STAT pathway is considered to be of great importance in the development of therapeutic interventions (2). The mammalian STAT family is made up of seven structurally and functionally related proteins named STAT1, 2, 3, 4, 5a, 5b, and 6 (3).…”

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confidence: 99%

Structural basis for DNA recognition by STAT6

Rodriguez

Niu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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STAT6 participates in classical IL-4/IL-13 signaling and stimulator of interferon genes-mediated antiviral innate immune responses. Aberrations in STAT6-mediated signaling are linked to development of asthma and diseases of the immune system. In addition, STAT6 remains constitutively active in multiple types of cancer. Therefore, targeting STAT6 is an attractive proposition for treating related diseases. Although a lot is known about the role of STAT6 in transcriptional regulation, molecular details on how STAT6 recognizes and binds specific segments of DNA to exert its function are not clearly understood. Here, we report the crystal structures of a homodimer of phosphorylated STAT6 core fragment (STAT6 CF ) alone and bound with the N3 and N4 DNA binding site. Analysis of the structures reveals that STAT6 undergoes a dramatic conformational change on DNA binding, which was further validated by performing molecular dynamics simulation studies and small angle X-ray scattering analysis. Our data show that a larger angle at the intersection where the two protomers of STAT meet and the presence of a unique residue, H415, in the DNAbinding domain play important roles in discrimination of the N4 site DNA from the N3 site by STAT6. H415N mutation of STAT6 CF decreased affinity of the protein for the N4 site DNA, but increased its affinity for N3 site DNA, both in vitro and in vivo. Results of our structure-function studies on STAT6 shed light on mechanism of DNA recognition by STATs in general and explain the reasons underlying STAT6's preference for N4 site DNA over N3.STAT6 | N4 site DNA recognition | JAK-STAT pathway | antiviral innate immunity | crystal structure P roteins belonging to the STAT family mediate transmission of signals of numerous cytokines and growth factors from the cell membrane to the nucleus via the classical JAK-STAT pathway (1). Malfunctions in this pathway are known to result in immune system disorder and cancers. Therefore, the JAK-STAT pathway is considered to be of great importance in the development of therapeutic interventions (2). The mammalian STAT family is made up of seven structurally and functionally related proteins named STAT1, 2, 3, 4, 5a, 5b, and 6 (3). All of the STAT proteins share a conserved domain organization (Fig. 1A).STAT6, an important member of the STAT family, plays a crucial role in the differentiation of Th2 cells and has been implicated in the development of asthma (4). This STAT is primarily stimulated by IL-4 and IL-13. A recent study reported that STAT6 plays a pivotal role in antiviral signaling initiated by host cells in response to viral infections (5). STAT6 could be activated by the stimulator of interferon genes/TBK1 cascade via phosphorylation of Y641. Intriguingly, residue S407 located in the DNA-binding domain (DBD) of STAT6 has been shown to be phosphorylated by TBK1. However, its implication for biological function of STAT6 is currently unknown (5). Thus, structural studies on STAT6 and its complex with DNA are essential to address several unanswered q...

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A STAT inhibitor patent review: progress since 2011

Cited by 51 publications

References 79 publications

Targeting Jurkat T Lymphocyte Leukemia Cells by an Engineered Interferon-Alpha Hybrid Molecule

Targeting Jurkat T Lymphocyte Leukemia Cells by an Engineered Interferon-Alpha Hybrid Molecule

Synthesis of new dithiolethione and methanethiosulfonate systems endowed with pharmaceutical interest

Structural basis for DNA recognition by STAT6

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