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Identification of MSA-2: An oral antitumor non-nucleotide STING agonist

2021; Springer Nature; Volume: 6; Issue: 1 Linguagem: Inglês

10.1038/s41392-020-00459-2

2095-9907

Jianhua Liu, Xu Huang, Jianxun Ding,

Immune Response and Inflammation

In a recent study in Science, Pan et al. 1 identified an orally available non-nucleotide human stimulator of interferon genes (STING) agonist, MSA-2 (benzothiophene oxobutanoic acid), with excellent safety tolerance in vivo.The noncovalently tethered dimers of MSA-2 could bind STING with nanomolar affinity, and the acidic tumor microenvironment would substantially increase the cell entry and retention of MSA-2 and its dimerized interaction with STING, thus leading to a superior antitumor potency of combined MSA-2 and anti-PD-1 treatments.This work has encouraged further design and discovery of clinical human STING agonists for systematic cancer therapy (Fig. 1).The success of immune checkpoint blockade therapy has significantly extended the survival of cancer patients, inspiring more efforts to explore other immune pathways that can be modulated pharmacologically to enhance the efficacies of immune checkpoint inhibitors (ICIs). 2 As a sensor of 2′,3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) at the endoplasmic reticulum, STING undergoes conformational change and activation via binding to cGAMP. 3 The activation of STING then induces increased expression of type I interferon through triggering downstream signals, leading to stimulation of robust antitumor immunity correlated with T cell infiltration.The first generation cyclic dinucleotide (CDN)-based STING agonist could induce inflammatory cytokines in both normal and tumor tissues, owing to its low selectivity.The combination of CDNbased STING agonists and ICIs demonstrated its therapeutic potentials in preclinical models, while the administration of STING agonists was only limited to intratumoral injection because of the omnipresent STING expression. 4Thus, the development of advanced STING agonists for systemic administration will significantly enhance their antitumor effectiveness clinically.Recently, Ramanjulu et al. 5 discovered a small molecule STING agonist that could be used for intravenous administration.The developed agonist not only resolved the challenge of drug administration but also extended the therapeutic potentials toward solid tumors.In this follow-up study, Pan et al. 1 developed a unique STING agonist, MSA-2, that displayed tumor targeting and could be administrated orally.To discover the optimal STING agonist, Pan et al. have developed a high-throughput screening strategy to identify cell-permeable STING agonists.After screening a library of around 2.4 million compounds, several molecules were identified, including MSA-2.MSA-2 was revealed to activate STING selectively and exhibited higher permeability than CDNs like MSA-1, a cGAMP analog.