Discovery of Non-Nucleotide Small-Molecule STING Agonists <i>via</i> Chemotype Hybridization

Cherney, Emily C.; Zhang, Liping; Lo, Julian B.; Huynh, Tram; Wei, Donna; Ahuja, Vijay T.; Quesnelle, Claude; Schieven, Gary L.; Futran, Alan; Locke, Gregory; Lin, Zheng‐Zhe; Monereau, Laura; Chaudhry, Charu; Blum, Jordan M.; Li, Sha; Fereshteh, Mark; Li-Wang, Bifang; Gangwar, Sanjeev; Pan, Chin Chen; Chong, Colin; Zhu, Xiaohan; Posy, Shana; Sack, John S.; Zhang, Ping; Ruzanov, Max; Harner, Mary J.; Akhtar, Fahad; Schroeder, G.; Vite, Gregory D.; Fink, Brian E.

doi:10.1021/acs.jmedchem.1c01986

Cited by 23 publications

(13 citation statements)

References 36 publications

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“…Human STING agonists , can be divided into two major groups: (1) CDNs and their derivates (ADU-S100, MK-1454, TAK-676, etc G10, , MSA-2, etc. , ). Due to the importance of the cGAS-STING pathway, there has been an increased interest in identifying new STING agonists with improved drug-like properties compared to the natural STING ligands.…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7-Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists

et al. 2022

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Cyclic dinucleotides (CDNs) are second messengers that activate stimulator of interferon genes (STING). The cGAS-STING pathway plays a promising role in cancer immunotherapy. Here, we describe the synthesis of CDNs containing 7-substituted 7-deazapurine moiety. We used mouse cyclic GMP−AMP synthase and bacterial dinucleotide synthases for the enzymatic synthesis of CDNs. Alternatively, 7-(het)aryl 7-deazapurine CDNs were prepared by Suzuki−Miyaura cross-couplings. New CDNs were tested in biochemical and cell-based assays for their affinity to human STING. Eight CDNs showed better activity than 2′3′-cGAMP, the natural ligand of STING. The effect on cytokine and chemokine induction was also evaluated. The best activities were observed for CDNs bearing large aromatic substituents that point above the CDN molecule. We solved four X-ray structures of complexes of new CDNs with human STING. We observed π−π stacking interactions between the aromatic substituents and Tyr240 that are involved in the stabilization of CDN-STING complexes.

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Section: Introductionmentioning

confidence: 99%

“… 26 ) and (2) synthetic non-nucleotide STING agonists (diABZI, 27 G10, 28 , 29 MSA-2, 30 etc. 31 , 32 ). Due to the importance of the cGAS-STING pathway, there has been an increased interest in identifying new STING agonists with improved drug-like properties compared to the natural STING ligands.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7-Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists

et al. 2022

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“…For example, the combination of programmed death (PD)-1 blocker and a STING agonist almost fully inhibited the solid tumor that was insensitive to single-agent treatment in a mouse model . In the past few years, several synthetic compounds with more advantageous pharmacokinetic properties were also developed. ,− To our knowledge, BDW568 is the first STING agonist that critically depends on residue A230 in STING. In the future, chemical modifications will be performed to BDW568 to improve its target selectivity and metabolic stability.…”

Section: Discussionmentioning

confidence: 99%

Cellular Target Deconvolution of Small Molecules Using a Selection-Based Genetic Screening Platform

et al. 2022

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Small-molecule drug target identification is an essential and often rate-limiting step in phenotypic drug discovery and remains a major challenge. Here, we report a novel platform for target identification of activators of signaling pathways by leveraging the power of a clustered regularly interspaced short palindromic repeats (CRISPR) knockout library. This platform links the expression of a suicide gene to the small-molecule-activated signaling pathway to create a selection system. With this system, loss-of-function screening using a CRISPR single-guide (sg) RNA library positively enriches cells in which the target has been knocked out. The identities of the drug targets and other essential genes required for the activity of small molecules of interest are then uncovered by sequencing. We tested this platform on BDW568, a newly discovered type-I interferon signaling activator, and identified stimulator of interferon genes (STING) as its target and carboxylesterase 1 (CES1) to be a key metabolizing enzyme required to activate BDW568 for target engagement. The platform we present here can be a general method applicable for target identification for a wide range of small molecules that activate different signaling pathways.

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“…The benzothiazinone STING agonist G10 was disclosed by VGTI and was obtained through high-throughput screening (HTS). Further structural modification and optimization of the benzothiazinone moiety rendered the indole compound C53 bound to a new site on the STING transmembrane domain, which mediated the oligomerization of STING dimer. − The reported non-nucleotide compound 2 with the pyrazolopyrimidine scaffold was designed by researchers in BMS through chemotype hybridization …”

Section: Introductionmentioning

confidence: 99%

Development of Orally Bioavailable Amidobenzimidazole Analogues Targeting Stimulator of Interferon Gene (STING) Receptor

et al. 2023

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Stimulator of interferon gene (STING) is a critical adaptor protein that has a pivotal role in triggering inherent immune responses to infection. STING-linked interferon production has been involved in anti-inflammation, anti-infection, and antitumor immunity. Herein, a series of amidobenzimidazole analogues as STING agonists were profiled for potency and drug-like properties. By structure-based modification and optimization based on mono-aminobenzimidazole (ABZI), analogues with nanomolar STING agonistic activities were obtained. Among them, compounds D59 and D61 significantly increased the transcription of IFN-β and proinflammatory cytokine CXCL10, as well as dramatically induced the phosphorylation of STING downstream proteins in THP1 cells. Furthermore, compound D61 exhibited favorable pharmacokinetic properties and metabolic stabilities. In a CT-26 syngeneic mice-bearing tumor model, D61 effectively inhibited tumor growth with good tolerance when administered via intratumoral, intravenous, intraperitoneal, and oral routes. This research on orally bioavailable amidobenzimidazole analogues expands the diversity of chemical structures of agonists for STING-mediated immunotherapy.

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Discovery of Non-Nucleotide Small-Molecule STING Agonists via Chemotype Hybridization

Cited by 23 publications

References 36 publications

Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7-Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists

Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7-Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists

Cellular Target Deconvolution of Small Molecules Using a Selection-Based Genetic Screening Platform

Development of Orally Bioavailable Amidobenzimidazole Analogues Targeting Stimulator of Interferon Gene (STING) Receptor

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