Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic

doi:10.1126/science.abb4255

GSTDTAP > 气候变化

DOI	10.1126/science.abb4255
	Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic
	Emily N. Chin; Chenguang Yu; Vincent F. Vartabedian; Ying Jia; Manoj Kumar; Ana M. Gamo; William Vernier; Sabrina H. Ali; Mildred Kissai; Daniel C. Lazar; Nhan Nguyen; Laura E. Pereira; Brent Benish; Ashley K. Woods; Sean B. Joseph; Alan Chu; Kristen A. Johnson; Philipp N. Sander; Francisco Martínez-Peña; Eric N. Hampton; Travis S. Young; Dennis W. Wolan; Arnab K. Chatterjee; Peter G. Schultz; H. Michael Petrassi; John R. Teijaro; Luke L. Lairson
	2020-08-21
发表期刊	Science
出版年	2020
英文摘要	Activation of the STING (stimulator of interferon genes) protein by cyclic dinucleotide metabolites plays a critical role in antitumor immunity. The development of synthetic STING agonists is therefore being pursued as a strategy for cancer therapy, but the inherent instability of dinucleotides has limited current efforts. Pan et al. and Chin et al. identified stable STING agonists that act in a “closed” conformation similar to the natural STING ligand, cyclic guanosine monophosphate–adenosine monophosphate (see the Perspective by Gajewski and Higgs). The small molecules can be given orally—an advantage over previously developed STING agonists, which required intratumoral administration. After oral or systemic administration in mice, the agonists activated STING and diverse immune cell types to promote antitumor immunity. These studies represent progress toward clinically viable STING agonists for cancer immunotherapy. Science , this issue p. [eaba6098][1], p. [993][2]; see also p. [921][3] Stimulator of interferon genes (STING) links innate immunity to biological processes ranging from antitumor immunity to microbiome homeostasis. Mechanistic understanding of the anticancer potential for STING receptor activation is currently limited by metabolic instability of the natural cyclic dinucleotide (CDN) ligands. From a pathway-targeted cell-based screen, we identified a non-nucleotide, small-molecule STING agonist, termed SR-717, that demonstrates broad interspecies and interallelic specificity. A 1.8-angstrom cocrystal structure revealed that SR-717 functions as a direct cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) mimetic that induces the same “closed” conformation of STING. SR-717 displayed antitumor activity; promoted the activation of CD8+ T, natural killer, and dendritic cells in relevant tissues; and facilitated antigen cross-priming. SR-717 also induced the expression of clinically relevant targets, including programmed cell death 1 ligand 1 (PD-L1), in a STING-dependent manner. [1]: /lookup/doi/10.1126/science.aba6098 [2]: /lookup/doi/10.1126/science.abb4255 [3]: /lookup/doi/10.1126/science.abc6622
领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/291222
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Emily N. Chin,Chenguang Yu,Vincent F. Vartabedian,et al. Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic[J]. Science,2020.
APA	Emily N. Chin.,Chenguang Yu.,Vincent F. Vartabedian.,Ying Jia.,Manoj Kumar.,...&Luke L. Lairson.(2020).Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic.Science.
MLA	Emily N. Chin,et al."Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic".Science (2020).