Identification of α‐Mangostin as an Agonist of Human STING

Zhang, Hongjie; Sun, Zhen; Pei, Junchen; Luo, Qinhong; Zeng, Xin; Li, Qinkai; Yáng, Zhèn; Quan, Jing

doi:10.1002/cmdc.201800481

Cited by 74 publications

(71 citation statements)

References 36 publications

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“…Meanwhile, Yibo Zhang et al identified a-Mangostin (Fig. 3g) sharing the same xanthone skeleton with DMXAA as a weak agonist of hSTING [141]. These findings provide a critical guide for future rational drug design of DMXAA variants with potential to enhance the interferons production in humans, which are needed for the development of anticancer therapies and vaccine adjuvants.…”

Section: Dmxaa and Its Analoguesmentioning

confidence: 91%

STING modulators: Predictive significance in drug discovery

Cui

Zhang

Cen

et al. 2019

European Journal of Medicinal Chemistry

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a b s t r a c tCyclic guanosine monophosphateeadenosine monophosphate synthase (cGAS) d stimulator of interferon genes (STING) signaling pathway plays the critical role in the immune response to DNA. Pharmacological modulation of the STING pathway has been well characterized both from structural and functional perspectives, which paves the way for the drug design of small modulators by medicinal chemists. Here, we outline recent progress in studies on the STING pathway, the structure and biological function of STING, the STING related disease, as well as the rationale and progress in the development of STING modulators. Our review demonstrates that STING is a promising drug target, and providing clues for the discovery of novel STING agonists and antagonists for the potential treatment of various disease including microbial infectious diseases, cancer, and autoimmune disease.

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Section: Dmxaa and Its Analoguesmentioning

confidence: 91%

STING modulators: Predictive significance in drug discovery

Cui

Zhang

Cen

et al. 2019

European Journal of Medicinal Chemistry

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“…Presently, there are eleven examples of non-CDN agonists ( Table 1 ), a majority of which share structural similarities with DMXAA ( Figure 5 ) [ 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 ]. GlaxoSmithKline (GSK) identified small molecule STING agonists, which shared a vital amidobenzimidazole component [ 91 ].…”

Section: Sting Activating Drugsmentioning

confidence: 99%

Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy

Aval

Pease

Sharma

et al. 2020

JCM

154

130

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Immune checkpoint inhibitors (ICI) have revolutionised cancer therapy. However, they have been effective in only a small subset of patients and a principal mechanism underlying immune-refractoriness is a ‘cold’ tumour microenvironment, that is, lack of a T-cell-rich, spontaneously inflamed phenotype. As such, there is a demand to develop strategies to transform the tumour milieu of non-responsive patients to one supporting T-cell-based inflammation. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway is a fundamental regulator of innate immune sensing of cancer, with potential to enhance tumour rejection through the induction of a pro-inflammatory response dominated by Type I interferons. Recognition of these positive immune-modulatory properties has rapidly elevated the STING pathway as a putative target for immunotherapy, leading to a myriad of preclinical and clinical studies assessing natural and synthetic cyclic dinucleotides and non-nucleotidyl STING agonists. Despite pre-clinical evidence of efficacy, clinical translation has resulted into disappointingly modest efficacy. Poor pharmacokinetic and physiochemical properties of cyclic dinucleotides are key barriers to the development of STING agonists, most of which require intra-tumoral dosing. Development of systemically administered non-nucleotidyl STING agonists, or conjugation with liposomes, polymers and hydrogels may overcome pharmacokinetic limitations and improve drug delivery. In this review, we summarise the body of evidence supporting a synergistic role of STING agonists with currently approved ICI therapies and discuss whether, despite the numerous obstacles encountered to date, the clinical development of STING agonist as novel anti-cancer therapeutics may still hold the promise of broadening the reach of cancer immunotherapy.

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“…Unlike the previous compounds, the remaining three compounds are capable of stimulating the human STING pathway. α‐Mangostin (Figure ), bearing a xanthone skeleton, was reported by Quan et al to have better human STING activity over that of mouse STING . BNBC and diABZI were identified via high‐throughput screening (HTS).…”

Section: Sting Agonistsmentioning

confidence: 99%

Agonists and inhibitors of the STING pathway: Potential agents for immunotherapy

Zhao

et al. 2019

Medicinal Research Reviews

110

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Since being discovered in 2008, the STING (stimulator of interferon genes) pathway has gradually been recognized as a central and promising target for immunotherapy. The STING pathway can be stimulated by cyclic dinucleotides (CDNs), leading to the type I interferons (IFN) production for immunotherapy for cancer or other diseases. However, the negative charges, hydrophilicity, and instability of CDNs have hindered their further applications. In addition, chronic activation of the STING pathway has been found to be involved in autoimmune diseases as IFN overproduction.Thus, research and development of STING agonists and inhibitors has been a hot field for the treatment of several diseases. The past several years, especially 2018, has seen increasingly rapid advances in this field. Here, this review summarizes the synthesis and modification of CDNs, the identification of nonnucleotide agonists, the recent progress in delivery systems and the medical applications, such as personalized vaccine adjuvants, in detail. In addition, in this review, we summarize the STING inhibitors' advances from two aspects, covalent, and noncovalent inhibitors. K E Y W O R D S agonist, cyclic dinucleotides, immunotherapy, inhibitor, STING

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Identification of α‐Mangostin as an Agonist of Human STING

Cited by 74 publications

References 36 publications

STING modulators: Predictive significance in drug discovery

STING modulators: Predictive significance in drug discovery

Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy

Agonists and inhibitors of the STING pathway: Potential agents for immunotherapy

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