Novel 7H-pyrrolo[2,3-d]pyrimidine derivatives as potent and orally active STAT6 inhibitors

Nagashima, S.; Hondo, Takeshi; Nagata, Hiroshi; Ogiyama, Takashi; Maeda, Jun; Hoshii, Hiroaki; Kontani, Toru; Kuromitsu, Sadao; Ohga, Keiko; Orita, Masaya; Ohno, Kazuki; Moritomo, Ayako; Shiozuka, Koichi; Furutani, Masako; Takeuchi, Makoto; Ohta, Mitsuaki; Tsukamoto, Shin‐ichi

doi:10.1016/j.bmc.2009.08.021

Cited by 43 publications

(18 citation statements)

References 16 publications

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“…Other notable inhibitors of STAT6 signalling include YM-341619, a derivative of 4-aminopyrimidine-5-carboxamide (IC 50 value of 0.70 nM) 155 , and AS1810722, a fused bicyclic pyrimidine derivative (IC 50 value of 2.4 nM) 156 . Both AS1810722 and YM-341619 are potent, orally active STAT6 inhibitors that could be developed for the treatment of STAT6-dependent allergic diseases, such as asthma.…”

Section: Inhibitors Of Stat6mentioning

confidence: 99%

Therapeutic modulators of STAT signalling for human diseases

Miklóssy

Hilliard

Turkson

2013

Nat Rev Drug Discov

363

334

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The signal transducer and activator of transcription (STAT) proteins have important roles in biological processes. The abnormal activation of STAT signalling pathways is also implicated in many human diseases, including cancer, autoimmune diseases, rheumatoid arthritis, asthma and diabetes. Over a decade has passed since the first inhibitor of a STAT protein was reported and efforts to discover modulators of STAT signalling as therapeutics continue. This Review discusses the outcomes of the ongoing drug discovery research endeavours against STAT proteins, provides perspectives on new directions for accelerating the discovery of drug candidates, and highlights the noteworthy candidate therapeutics that have progressed to clinical trials.

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Section: Inhibitors Of Stat6mentioning

confidence: 99%

Therapeutic modulators of STAT signalling for human diseases

Miklóssy

Hilliard

Turkson

2013

Nat Rev Drug Discov

363

334

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“…When administered to the airway prior to each allergen challenge, the STAT6 inhibitor localizes to airway epithelial cells and impairs Ag-induced pulmonary eosinophilia, goblet cell hyperplasia, IL-13 production in the airways, AHR, and induction of eotaxin-1 and mucus genes in the lung 108 . Similar effects on AAD have been shown with small molecule inhibitors of STAT6 109 . Moreover, a topical STAT6 oligodeoxynucleotide ointment reduced the severity of the inflammatory skin lesions present in patients with atopic dermatitis 110 .…”

Section: Stat6mentioning

confidence: 73%

Wheezing and itching

Glosson

Bruns²,

Kaplan³

2012

JAK-STAT

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The development of allergic inflammation requires the orchestration of gene expression from the inflamed tissue and from the infiltrating immune cells. Since many of the cytokines that promote allergic inflammation signal through hematopoietin family receptors, the Signal Transducer and Activator of Transcription (STAT) family have obligate roles in pro-allergic cytokine-induced gene regulation in multiple cell types. In this review, we summarize work defining the contribution of each of the STAT family members to the development of allergic inflammation, using data from mouse models of allergic inflammation, studies on patient samples and correlations with single nucleotide polymorphisms in STAT genes.

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“…Therefore, STAT6 may be an excellent therapeutic target for allergic asthma. Small-molecule inhibitors, such as AS1517499 [14,15] and AS180772 [16], inhibited Th2 T-cell differentiation in vitro without affecting Th1-cell differentiation and eosinophil infiltration in antigen-induced mouse asthma 'models'. Additionally, Kaempferol, a natural flavonol, inhibits IL-4-induced STAT6 activation by specifically targeting JAK3 [17].…”

Section: Stat6mentioning

confidence: 99%

Identifying and testing potential new anti-asthma agents

Fang

Corrigan

Sun

2011

Expert Opinion on Drug Discovery

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As targeting single Th2 cytokines and their receptors has been shown to have limited clinical benefit, it is important to identify and test potential new therapeutic agents. Recent studies suggest that blockade of IgE synthesis, its interaction with its receptors and downstream signaling, identification of molecular targets in innate immune and airways structural cells, and fresh anti-neutrophil strategies should be prominent among these. Further studies are required to clarify the relationship between airways remodeling and asthma severity so that appropriate patients may be targeted.

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Novel 7H-pyrrolo[2,3-d]pyrimidine derivatives as potent and orally active STAT6 inhibitors

Cited by 43 publications

References 16 publications

Therapeutic modulators of STAT signalling for human diseases

Therapeutic modulators of STAT signalling for human diseases

Wheezing and itching

Identifying and testing potential new anti-asthma agents

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