Cited by 709interferon and immune responsesCancer Immunotherapy and BiomarkersImmunotherapy and Immune Responses

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An orally available non-nucleotide STING agonist with antitumor activity

Pan, Bo-Sheng, Perera, Samanthi A., Piesvaux, Jennifer A., Presland, Jeremy P., Schroeder, Gottfried K., Cumming, Jared N., Trotter, B. Wesley, Altman, Michael D., Buevich, Alexei V., Cash, Brandon, Cemerski, Saso, Chang, Wonsuk, Chen, Yiping, Dandliker, Peter J., Feng, Guo, Haidle, Andrew, Henderson, Timothy, Jewell, James, Kariv, Ilona, Knemeyer, Ian, Kopinja, Johnny, Lacey, Brian M., Laskey, Jason, Lesburg, Charles A., Liang, Rui, Long, Brian J., Lu, Min, Ma, Yanhong, Minnihan, Ellen C., O’Donnell, Greg, Otte, Ryan, Price, Laura, Rakhilina, Larissa, Sauvagnat, Berengere, Sharma, Sharad, Tyagarajan, Sriram, Woo, Hyun, Wyss, Daniel F., Xu, Serena, Bennett, David Jonathan, Addona, George H.·2020·Science

DOI 10.1126/science.aba6098

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Abstract

Targeting STING for cancer therapy: 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 , p. 993 ; see also p. 921

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Additional file 3 of TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro
Duan, Q.-Q., Wang, H., Su, W.-M., Gu, X., Shen, X.-F., Jiang, Z., Ren, Y.-L., Cao, B., Li, G.-B., Wang, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26689454
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Additional file 4 of Combination of oral STING agonist MSA-2 and anti-TGF-β/PD-L1 bispecific antibody YM101: a novel immune cocktail therapy for non-inflamed tumors
Yi, M., Niu, M., Wu, Y., Ge, H., Jiao, D., Zhu, S., Zhang, J., Yan, Y., Zhou, P., Chu, Q., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21303575
Additional file 9 of Combination of oral STING agonist MSA-2 and anti-TGF-β/PD-L1 bispecific antibody YM101: a novel immune cocktail therapy for non-inflamed tumors
Yi, M., Niu, M., Wu, Y., Ge, H., Jiao, D., Zhu, S., Zhang, J., Yan, Y., Zhou, P., Chu, Q., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21303590
Additional file 4 of TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro
Duan, Q.-Q., Wang, H., Su, W.-M., Gu, X., Shen, X.-F., Jiang, Z., Ren, Y.-L., Cao, B., Li, G.-B., Wang, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26689457
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Additional file 3 of STING controls opioid-induced itch and chronic itch via spinal tank-binding kinase 1-dependent type I interferon response in mice
Li, N., Wang, C., Zhao, Y., Wang, Y., Gao, T., Yu, Y., Wang, G., & Zhang, L. (2023) · Figshare · doi:10.6084/m9.figshare.22724213
Additional file 15 of Combination of oral STING agonist MSA-2 and anti-TGF-β/PD-L1 bispecific antibody YM101: a novel immune cocktail therapy for non-inflamed tumors
Yi, M., Niu, M., Wu, Y., Ge, H., Jiao, D., Zhu, S., Zhang, J., Yan, Y., Zhou, P., Chu, Q., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21303563
Additional file 13 of Combination of oral STING agonist MSA-2 and anti-TGF-β/PD-L1 bispecific antibody YM101: a novel immune cocktail therapy for non-inflamed tumors
Yi, M., Niu, M., Wu, Y., Ge, H., Jiao, D., Zhu, S., Zhang, J., Yan, Y., Zhou, P., Chu, Q., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21303557
Additional file 2 of Combination of oral STING agonist MSA-2 and anti-TGF-β/PD-L1 bispecific antibody YM101: a novel immune cocktail therapy for non-inflamed tumors
Yi, M., Niu, M., Wu, Y., Ge, H., Jiao, D., Zhu, S., Zhang, J., Yan, Y., Zhou, P., Chu, Q., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21303569
Additional file 1 of TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro
Duan, Q.-Q., Wang, H., Su, W.-M., Gu, X., Shen, X.-F., Jiang, Z., Ren, Y.-L., Cao, B., Li, G.-B., Wang, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25347106
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Additional file 6 of Combination of oral STING agonist MSA-2 and anti-TGF-β/PD-L1 bispecific antibody YM101: a novel immune cocktail therapy for non-inflamed tumors
Yi, M., Niu, M., Wu, Y., Ge, H., Jiao, D., Zhu, S., Zhang, J., Yan, Y., Zhou, P., Chu, Q., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21303581
Additional file 1 of STING controls opioid-induced itch and chronic itch via spinal tank-binding kinase 1-dependent type I interferon response in mice
Li, N., Wang, C., Zhao, Y., Wang, Y., Gao, T., Yu, Y., Wang, G., & Zhang, L. (2023) · Figshare · doi:10.6084/m9.figshare.22724207
Additional file 2 of TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro
Duan, Q.-Q., Wang, H., Su, W.-M., Gu, X., Shen, X.-F., Jiang, Z., Ren, Y.-L., Cao, B., Li, G.-B., Wang, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25347282
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Additional file 14 of Combination of oral STING agonist MSA-2 and anti-TGF-β/PD-L1 bispecific antibody YM101: a novel immune cocktail therapy for non-inflamed tumors
Yi, M., Niu, M., Wu, Y., Ge, H., Jiao, D., Zhu, S., Zhang, J., Yan, Y., Zhou, P., Chu, Q., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21303560
Additional file 1 of Combination of oral STING agonist MSA-2 and anti-TGF-β/PD-L1 bispecific antibody YM101: a novel immune cocktail therapy for non-inflamed tumors
Yi, M., Niu, M., Wu, Y., Ge, H., Jiao, D., Zhu, S., Zhang, J., Yan, Y., Zhou, P., Chu, Q., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21303566
Additional file 10 of Combination of oral STING agonist MSA-2 and anti-TGF-β/PD-L1 bispecific antibody YM101: a novel immune cocktail therapy for non-inflamed tumors
Yi, M., Niu, M., Wu, Y., Ge, H., Jiao, D., Zhu, S., Zhang, J., Yan, Y., Zhou, P., Chu, Q., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21303548
Additional file 5 of Combination of oral STING agonist MSA-2 and anti-TGF-β/PD-L1 bispecific antibody YM101: a novel immune cocktail therapy for non-inflamed tumors
Yi, M., Niu, M., Wu, Y., Ge, H., Jiao, D., Zhu, S., Zhang, J., Yan, Y., Zhou, P., Chu, Q., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21303578
Additional file 1 of Medicinal plant-derived mtDNA via nanovesicles induces the cGAS-STING pathway to remold tumor-associated macrophages for tumor regression
Liu, J., Xiang, J., Jin, C., Ye, L., Wang, L., Gao, Y., Lv, N., Zhang, J., You, F., Qiao, H., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22623830
Additional file 3 of Combination of oral STING agonist MSA-2 and anti-TGF-β/PD-L1 bispecific antibody YM101: a novel immune cocktail therapy for non-inflamed tumors
Yi, M., Niu, M., Wu, Y., Ge, H., Jiao, D., Zhu, S., Zhang, J., Yan, Y., Zhou, P., Chu, Q., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21303572
Additional file 2 of STING controls opioid-induced itch and chronic itch via spinal tank-binding kinase 1-dependent type I interferon response in mice
Li, N., Wang, C., Zhao, Y., Wang, Y., Gao, T., Yu, Y., Wang, G., & Zhang, L. (2023) · Figshare · doi:10.6084/m9.figshare.22724210

Authors: Pan, B.-S., Perera, S. A., Piesvaux, J. A., Presland, J. P., Schroeder, G. K., Cumming, J. N., Trotter, B. W., Altman, M. D., Buevich, A. V., Cash, B., Cemerski, S., Chang, W., Chen, Y., Dandliker, P. J., Feng, G., Haidle, A., Henderson, T., Jewell, J., Kariv, I., Knemeyer, I., Kopinja, J., Lacey, B. M., Laskey, J., Lesburg, C. A., Liang, R., Long, B. J., Lu, M., Ma, Y., Minnihan, E. C., O’Donnell, G., Otte, R., Price, L., Rakhilina, L., Sauvagnat, B., Sharma, S., Tyagarajan, S., Woo, H., Wyss, D. F., Xu, S., Bennett, D. J., & Addona, G. H.
Affiliations: Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Department of Discovery Oncology, Merck & Co., Inc., Kenilworth, NJ, USA.
Department of Quantitative Biosciences, Merck & Co., Inc., Kenilworth, NJ, USA.
Corresponding author: Pan, Bo-Sheng
Perera, Samanthi A.
Piesvaux, Jennifer A.
Presland, Jeremy P.
Schroeder, Gottfried K.
Cumming, Jared N.
Trotter, B. Wesley
Bennett, David Jonathan
Addona, George H.
ORCID: Pan, Bo-Sheng
Perera, Samanthi A.
Piesvaux, Jennifer A.
Presland, Jeremy P.
Schroeder, Gottfried K.
Cumming, Jared N.
Trotter, B. Wesley
Buevich, Alexei V.
Cash, Brandon
Cemerski, Saso
Chang, Wonsuk
Chen, Yiping
Dandliker, Peter J.
Feng, Guo
Haidle, Andrew
Kariv, Ilona
Knemeyer, Ian
Kopinja, Johnny
Lacey, Brian M.
Laskey, Jason
Lesburg, Charles A.
Liang, Rui
Long, Brian J.
Lu, Min
Minnihan, Ellen C.
O’Donnell, Greg
Otte, Ryan
Price, Laura
Rakhilina, Larissa
Sauvagnat, Berengere
Sharma, Sharad
Tyagarajan, Sriram
Woo, Hyun
Wyss, Daniel F.
Bennett, David Jonathan
Addona, George H.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2020-08-21
Volume: 369
Issue: 6506
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.aba6098
OpenAlex: W3061136593
Cited by: 694
References: 36
Citations by year: 2026: 127 · 2025: 159 · 2024: 124 · 2023: 107 · 2022: 102 · 2021: 61 · 2020: 14
FWCI: 25.83
Type: journal article
Language: en
Open access: closed
Locations: Science (publishedVersion)
PubMed (publishedVersion)
DORA PSI (Paul Scherrer Institute) (submittedVersion)
Topics: Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords: STING agonist, MSA-2, oral drug delivery, innate immunity, antitumor immunity, interferon-beta, anti-PD-1 combination therapy, covalent dimers, tumor microenvironment acidification, cancer immunotherapy
MeSH terms: STING Protein, Administration, Oral, Animals, Antineoplastic Agents, Humans, Membrane Proteins

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An orally available non-nucleotide STING agonist with antitumor activity

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