Science: Significant progress! Oral non-nucleoside STING astrologist MSA-2 showed significant anti-tumor activity.

August 26, 2020 /---STING protein is activated by its natural ligand--- cyclic guanosine monophosphate-adenosine monophosphate, cGAMP), triggering a signal transductive reaction that induces the release of type I interferon and other inflammatory cytokines.
interferons controlled by STING to produce participatory antiviral defenses and anti-tumor immune responses.
the use of drugs to activate STING is considered a promising cancer treatment strategy.
first generation STING exciter is a cyclic dinucleotide (CDN) analogoid of cGAMP.
when given throughout the body in animal models, they induce inflammatory cytokine expression in tumors and normal tissues due to ubiquitous STING expression.
, CDN-based STING astrologists, which are currently undergoing clinical trials, are given by direct intra-tumor injection, limiting their use to a few tumors.
in order to apply them to a wide variety of cancers, STING astrologists are needed for systemic dosing and priority targeting of tumors.
a new study, researchers from Merck in the United States found that a previously unknown compound (MSA-2) can be systematically drugged and prioritized to target tumors through its unique mechanism of action.
addition, MSA-2 is easy to take oral, which is an ideal route due to its convenience and low cost.
study was published in the August 21, 2020 issue of the journal Science under the title "An orally available non-nucleotide STING agonist with antitumor activity."
STING astrist MSA-2, pictured from Science, 2020, doi:10.1126/science.aba6098.
MSA-2 is identified in ideopaedic screening of chemical inducers that promote the secretion of beta interferon.
in cellless trials, MSA-2 can be combined with STING in humans and mice.
MSA-2 showed similar oral and supposition exposure in mice.
, MSA-2 induces elevated beta interferon in plasma and tumors through two drug-induced pathways.
well-to-do MSA-2 course induced tumors to subside in mice with MC38 congener tumors.
mice that showed complete retreat were resistant to re-vaccination of MC38 cells, suggesting that a long-lasting anti-tumor immune response was established.
in tumor models with moderate or poor PD-1 blocking response, the combination of MSA-2 and anti-PD-1 antibodies was used better than single-drug therapy in inhibiting tumor growth and prolonging survival.
the structure of the model shows that MSA-2 combines with STING in the form of non-co-priced dmogeneity and presents a closed structure.
two monomers of each combined MSA-2 and STING co-sourced djumer.
This simplest model can explain all the observed equilibrium and dynamic behavior of MSA-2: MSA-2 exists in a solution in the form of monomers and non-common price diomer, in a state of equilibrium with a strong preference for monomers;
model is further supported by the fact that the co-priced coupled binary of MSA-2 similarts shows nanomolar affinity for STING.
simulations and experimental analysis predict that, as a weak acid, MSA-2 will exhibit greater cell effectiveness in the acidified tumor microencology than in normal tissues, due to increased cell entry and retention, coupled with an inherent increase in STING occupancy dependence on MSA-2 concentrations.
priority activation of MSA-2 in tumors may contribute significantly to the observing of good in vivo anti-tumor activity and tolerance of this compound.
, in this new study, the authors found that MSA-2 is an oral human STING inflammatory agent that describes its identification, anti-tumor properties and mechanisms of action in the body.
MSA-2 may prove valuable for the discovery and design of STING astrists suitable for clinical system dosing.
(bioon.com) Reference: 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.