Orally Available Non-Nucleotide STING Agonist MSA-2 Demonstrates Potent Antitumor Activity
Aug 26, 2020 13:48
CST Updated
13:48
Merck Group
Pharmaceutical R&D Developer
August 26, 2020 News/Bio ValleyBIOON/---The STING protein is activated by its natural ligand, cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), triggering signal transduction responses that induce the release of type I interferons and other pro-inflammatory cytokines. STING-controlled interferon production is involved in antiviral defense and anti-TumorImmune Response. Activating STING with drugs is considered a promising cancer therapy strategy.
First-generation STING agonists are cyclic dinucleotide (CDN) analogs of cGAMP. When administered systemically in animal models, they induce inflammatory cytokine expression equivalently in both tumor and normal tissues due to the ubiquitous expression of STING. Therefore, currently ongoingClinical TrialCDN-based STING agonists are all administered via direct intratumoral injection, which limits their application to a few types of tumors. To apply them to a wide variety of cancers, it is necessary to develop formulations suitable for systemic administration with preferential targetingTumorSTING agonists.
In a new study, researchers from Merck in the United States discovered a previously unknown compound (MSA-2) that can be administered systemically and preferentially targets through its unique mechanism of actionTumorFurthermore, MSA-2 is amenable to oral administration, which is an ideal route of administration due to its convenience and low cost. The relevant findings were published in the journal Science on August 21, 2020, in a paper titled “An orally available non-nucleotide STING agonist with antitumor activity”.
MSA-2 was identified through phenotypic screening for chemical inducers of interferon-beta secretion. In cell-free assays, MSA-2 binds to both human and murine STING. MSA-2 exhibits comparable exposure profiles in mice following oral and subcutaneous administration. In tumor-bearing mice, MSA-2 induces elevated levels of interferon-beta in both plasma and tumors via both routes of administration. A well-tolerated course of MSA-2 treatment induced tumor regression in mice bearing MC38 syngeneic tumors. The majority of mice exhibiting complete regression were resistant to rechallenge with MC38 cells, indicating the establishment of a durable antitumor immune response. In tumor models with moderate or poor responses to PD-1 blockade, the combination of MSA-2 and anti-PD-1 antibody inhibitedTumorSuperior to monotherapy in terms of growth and prolonging survival.
Structural studies indicate that MSA-2 binds to STING as a non-covalent dimer and adopts a closed conformation. Each bound MSA-2 interacts with both monomers of the STING homodimer. This simplest model can explain all observed equilibrium and kinetic behaviors of MSA-2: MSA-2 exists in solution as monomers and non-covalent dimers, in an equilibrium strongly favoring the monomeric state; MSA-2 monomers cannot bind STING, whereas non-covalent MSA-2 dimers bind STING with nanomolar affinity. Covalently linked dimers of MSA-2 analogs exhibitNanomolar affinity, which further supports this model.
Simulation and experimental analysis predict that, as a weak acid, MSA-2 will exhibit greater cellular potency in the acidic tumor microenvironment than in normal tissues, due to increased cellular uptake and retention, combined with the inherently steep, concentration-dependent increase in STING occupancy by MSA-2. The preferential activation of STING by MSA-2 in tumors may largely contribute to the observed favorable in vivo anti-TumorActivity and Tolerability.
In summary, in this new study, the authors identified MSA-2 as an oral human STING agonist and described its identification and in vivo anti-TumorCharacteristics and Mechanism of Action. MSA-2 may prove valuable for the discovery and design of human STING agonists suitable for systemic clinical administration. (Bioon.com)
References:
1.Bo-Sheng Pan et al. An orally available non-nucleotide STING agonist with antitumor activity. Science, 2020, doi:10.1126/science.aba6098.
2.Thomas F. Gajewski et al. Immunotherapy with a sting. Science, 2020, doi:10.1126/science.abc6622.
First-generation STING agonists are cyclic dinucleotide (CDN) analogs of cGAMP. When administered systemically in animal models, they induce inflammatory cytokine expression equivalently in both tumor and normal tissues due to the ubiquitous expression of STING. Therefore, currently ongoingClinical TrialCDN-based STING agonists are all administered via direct intratumoral injection, which limits their application to a few types of tumors. To apply them to a wide variety of cancers, it is necessary to develop formulations suitable for systemic administration with preferential targetingTumorSTING agonists.
In a new study, researchers from Merck in the United States discovered a previously unknown compound (MSA-2) that can be administered systemically and preferentially targets through its unique mechanism of actionTumorFurthermore, MSA-2 is amenable to oral administration, which is an ideal route of administration due to its convenience and low cost. The relevant findings were published in the journal Science on August 21, 2020, in a paper titled “An orally available non-nucleotide STING agonist with antitumor activity”.
STING agonist MSA-2. Image from Science, 2020, doi:10.1126/science.aba6098.
MSA-2 was identified through phenotypic screening for chemical inducers of interferon-beta secretion. In cell-free assays, MSA-2 binds to both human and murine STING. MSA-2 exhibits comparable exposure profiles in mice following oral and subcutaneous administration. In tumor-bearing mice, MSA-2 induces elevated levels of interferon-beta in both plasma and tumors via both routes of administration. A well-tolerated course of MSA-2 treatment induced tumor regression in mice bearing MC38 syngeneic tumors. The majority of mice exhibiting complete regression were resistant to rechallenge with MC38 cells, indicating the establishment of a durable antitumor immune response. In tumor models with moderate or poor responses to PD-1 blockade, the combination of MSA-2 and anti-PD-1 antibody inhibitedTumorSuperior to monotherapy in terms of growth and prolonging survival.
Structural studies indicate that MSA-2 binds to STING as a non-covalent dimer and adopts a closed conformation. Each bound MSA-2 interacts with both monomers of the STING homodimer. This simplest model can explain all observed equilibrium and kinetic behaviors of MSA-2: MSA-2 exists in solution as monomers and non-covalent dimers, in an equilibrium strongly favoring the monomeric state; MSA-2 monomers cannot bind STING, whereas non-covalent MSA-2 dimers bind STING with nanomolar affinity. Covalently linked dimers of MSA-2 analogs exhibitNanomolar affinity, which further supports this model.
Simulation and experimental analysis predict that, as a weak acid, MSA-2 will exhibit greater cellular potency in the acidic tumor microenvironment than in normal tissues, due to increased cellular uptake and retention, combined with the inherently steep, concentration-dependent increase in STING occupancy by MSA-2. The preferential activation of STING by MSA-2 in tumors may largely contribute to the observed favorable in vivo anti-TumorActivity and Tolerability.
In summary, in this new study, the authors identified MSA-2 as an oral human STING agonist and described its identification and in vivo anti-TumorCharacteristics and Mechanism of Action. MSA-2 may prove valuable for the discovery and design of human STING agonists suitable for systemic clinical administration. (Bioon.com)
References:
1.Bo-Sheng Pan et al. An orally available non-nucleotide STING agonist with antitumor activity. Science, 2020, doi:10.1126/science.aba6098.
2.Thomas F. Gajewski et al. Immunotherapy with a sting. Science, 2020, doi:10.1126/science.abc6622.