Identification of Novel Carbocyclic Pyrimidine Cyclic Dinucleotide STING Agonists for Antitumor Immunotherapy Using Systemic Intravenous Route

Vyskočil, Štěpán; Cardin, D. J.; Ciavarri, Jeffrey P.; Conlon, Joe; Cullis, Courtney; England, Dylan B.; Gershman, Rachel E.; Gigstad, Kenneth M.; Gipson, Krista; Gould, Alexandra E.; Greenspan, Paul D.; Griffin, Robert J.; Gulavita, Nanda K.; Harrison, Sean; Hu, Zhigen; Hu, Yongbo; Hata, Akito; Huang, Jian; Huang, Shih-Chung; Janowick, Dave; Jones, Matthew R.; Kolev, Vihren N.; Langston, Steven; Lee, Jun Young; Li, Gang; Lok, David; Ma, Li‐Ting; Mai, Doanh; Malley, Jenna; Matsuda, Atsushi; Mizutani, Hirotake; Mizutani, Masato; Molchanova, N.; Nunes, Elise; Pusalkar, Sandeep; Renou, Christelle; Rowland, Scott K.; Sato, Yosuke; Shaw, Michael H.; Shen, Linlin; Shi, Zhan; Skene, R.J.; Soucy, François; Stroud, Steve; Xu, He N.; Xu, Tianlin; Abu-Yousif, Adnan O.; Zhang, Ji

doi:10.1021/acs.jmedchem.1c00374

Cited by 28 publications

(24 citation statements)

References 36 publications

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“…, ∼2 min in mice), which, along with their poor drug-like properties, significantly limits their overall exposure, tissue distribution, and activity. ,, Accordingly, systemically administered CDNs have proven largely ineffective in limiting tumor growth in mouse tumor models. ,, To improve efficacy for intravenous administration, Vyskocil et al approached some of these limitations by developing a novel carbocyclic STING agonist ( i.e. , 15a ), which comprises carbocyclic nucleotides, cyclopentane instead of ribose, and the imidazole portion of adenine replaced with a pyrimidine ring (Figure ). 15a exhibited a half-life of ∼23.4 min in BALB/c mice when administered intravenously at 1 mg/kg with systemic exposure ( i.e.…”

Section: Drug Delivery Barriers and Pharmacological Challengesmentioning

confidence: 99%

“…328,390,391 Accordingly, systemically administered CDNs have proven largely ineffective in limiting tumor growth in mouse tumor models. 24,196,390 To improve efficacy for intravenous administration, Vyskocil et al approached some of these limitations by developing a novel carbocyclic STING agonist (i.e., 15a), which comprises carbocyclic nucleotides, cyclopentane instead of ribose, and the imidazole portion of adenine replaced with a pyrimidine ring 366 (Figure 12). 15a exhibited a half-life of ∼23.4 min in BALB/c mice when administered intravenously at 1 mg/kg with systemic exposure (i.e., 3.9 μM in plasma collected 5 min after in injection) at or above cellular concentrations required for its activity.…”

Section: Utility and Challenges With Systemic Administration Of Sting...mentioning

confidence: 99%

“…The CDNs modified to include fluorine substitutions for 2′-hydrogens or 2′hydroxyl groups on the pentose rings (i.e., 2′-F-c-di-GMP,363 dithio-2′-F-cAIMP (compound 53),364 and the 3′3′-c-Di(2′F,2′dAMP) prodrug365 ) exhibit improved membrane permeability as well as stability against enzymatic degradation. The carbocyclic STING agonist, 15a, which comprises carbocyclic nucleotides, cyclopentane instead of ribose, and the imidazole portion of adenine replaced with a pyrimidine ring, exhibits significantly improved STING binding, cellular activity, and membrane permeability 366.…”

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confidence: 99%

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Chemical and Biomolecular Strategies for STING Pathway Activation in Cancer Immunotherapy

2022

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The stimulator of interferon genes (STING) cellular signaling pathway is a promising target for cancer immunotherapy. Activation of the intracellular STING protein triggers the production of a multifaceted array of immunostimulatory molecules, which, in the proper context, can drive dendritic cell maturation, antitumor macrophage polarization, T cell priming and activation, natural killer cell activation, vascular reprogramming, and/or cancer cell death, resulting in immune-mediated tumor elimination and generation of antitumor immune memory. Accordingly, there is a significant amount of ongoing preclinical and clinical research toward further understanding the role of the STING pathway in cancer immune surveillance as well as the development of modulators of the pathway as a strategy to stimulate antitumor immunity. Yet, the efficacy of STING pathway agonists is limited by many drug delivery and pharmacological challenges. Depending on the class of STING agonist and the desired administration route, these may include poor drug stability, immunocellular toxicity, immune-related adverse events, limited tumor or lymph node targeting and/or retention, low cellular uptake and intracellular delivery, and a complex dependence on the magnitude and kinetics of STING signaling. This review provides a concise summary of the STING pathway, highlighting recent biological developments, immunological consequences, and implications for drug delivery. This review also offers a critical analysis of an expanding arsenal of chemical strategies that are being employed to enhance the efficacy, safety, and/or clinical utility of STING pathway agonists and lastly draws attention to several opportunities for therapeutic advancements.

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Section: Drug Delivery Barriers and Pharmacological Challengesmentioning

confidence: 99%

Section: Utility and Challenges With Systemic Administration Of Sting...mentioning

confidence: 99%

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confidence: 99%

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Chemical and Biomolecular Strategies for STING Pathway Activation in Cancer Immunotherapy

2022

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“…[ 29a ] The recent study showed that modification of CDN‐mimetic CDNs with a pyrimidine ring improved pharmacokinetics as well as binding affinity, thus enabling systemic administration. [ 31 ] In comparison to the chemical structure of cGAMP, phosphoester was replaced with phosphothioester while the adenine moiety from one of the bases was modified with pyrimidine rings. [ 31 ] This CDN‐mimetic STING agonist was endowed with greater binding affinity with human STING protein and prolonged half‐life in blood plasma, thus showing meaningful anti‐tumor responses in colorectal tumor models.…”

Section: Cgas‐sting‐activating Moleculesmentioning

confidence: 99%

Harnessing cGAS‐STING Pathway for Cancer Immunotherapy: From Bench to Clinic

Lee

Huntoon

Kang

et al. 2022

Advanced Therapeutics

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Recent advances in cancer immunotherapy have accomplished clinical successes in certain cancer models over the past decade. However, cancer treatments with adoptive cell transfer or immune checkpoint blockade (ICB) have shown critical limitations against solid tumors, which comprise the majority of human cancers. Thus, novel cancer immunotherapy which harnesses innate immunity process may be required in these tumor types. Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, one of the innate immune sensors, has gained interest in the field of immuno-oncology as activation of this pathway can drive both innate and adaptive immune responses among immunosuppressive tumor microenvironments. Recently, various cGAS-STING-activating strategies have been intensively investigated to achieve durable and widespread therapeutic responses in in vivo models. These meaningful preclinical outcomes have enabled several clinical trials. This review discusses agents targeting various aspects of the cGAS-STING pathway in cancer immunotherapy from benchtop to bedside. Moreover, various approaches to improve the clinical feasibility of cGAS-STING-activating strategies are delineated.

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“…ML00960317 is a STING agonist with a synthetic CDN structure (Fig. 1), and it has shown potent antitumor activity in nonclinical tumor models by inducing robust innate and adaptive immune responses (5). Generally, endogenous cGAMP and its synthetic analogs such as ML00960317 have moderate-to-high molecular weight (> 400) and low permeability (Supplemental Table 6) and therefore, uptake transporters play an obligatory role in their pharmacological effects in target cells (6,7).…”

Section: Introductionmentioning

confidence: 99%

Sinusoidal Organic Anion-Transporting Polypeptide 1B1/1B3 and Bile Canalicular Multidrug Resistance-Associated Protein 2 Play an Essential Role in the Hepatobiliary Disposition of a Synthetic Cyclic Dinucleotide (STING Agonist)

Sandoval

Chuang

Fallon

et al. 2022

AAPS J

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The liver is central to the elimination of many drugs from the body involving multiple processes and understanding of these processes is important to quantitively assess hepatic clearance of drugs. The synthetic STING (STimulator of INterferon Genes protein) agonist is a new class of drugs currently being evaluated in clinical trials as a potential anticancer therapy. In this study, we used ML00960317 (synthetic STING agonist) to investigate the hepatobiliary disposition of this novel molecular entity. A bile-duct cannulated (BDC) rat study indicated that biliary excretion is the major route of elimination for ML00960317 (84% of parent dose in bile). The human biliary clearance using in vitro sandwich cultured human hepatocyte model predicted significant biliary excretion of ML00960317 (biliary excretion index (BEI) of 47%). Moreover, the transport studies using transporter expressing cell lines, hepatocytes, and membrane vesicles indicated that ML00960317 is a robust substrate of OATP1B1, OATP1B3, and MRP2. Using relative expression factor approach, the combined contribution of OATP1B1 (fraction transported (ft) = 0.62) and OATP1B3 (ft = 0.31) was found to be 93% of the active uptake clearance of ML00960317 into the liver. Furthermore, OATP1B1 and OATP1B3-mediated uptake of ML00960317 was inhibited by rifampicin with IC50 of 6.5 and 2.3 μM, respectively indicating an in vivo DDI risk (R value of 1.5 and 2.5 for OATP1B1 and OATP1B3, respectively). These results highlighted an important role of OATP1B1, OATP1B3, and MRP2 in the hepatobiliary disposition of ML00960317. These pathways may act as rate-determining steps in the hepatic clearance of ML00960317 thus presenting clinical DDI risk. Graphical Abstract

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Identification of Novel Carbocyclic Pyrimidine Cyclic Dinucleotide STING Agonists for Antitumor Immunotherapy Using Systemic Intravenous Route

Cited by 28 publications

References 36 publications

Chemical and Biomolecular Strategies for STING Pathway Activation in Cancer Immunotherapy

Chemical and Biomolecular Strategies for STING Pathway Activation in Cancer Immunotherapy

Harnessing cGAS‐STING Pathway for Cancer Immunotherapy: From Bench to Clinic

Sinusoidal Organic Anion-Transporting Polypeptide 1B1/1B3 and Bile Canalicular Multidrug Resistance-Associated Protein 2 Play an Essential Role in the Hepatobiliary Disposition of a Synthetic Cyclic Dinucleotide (STING Agonist)

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