An orally available non-nucleotide STING agonist with antitumor activity

Abstract

Pharmacological activation of the STING (stimulator of interferon genes)–controlled innate immune pathway is a promising therapeutic strategy for cancer. Here we report the identification of MSA-2, an orally available non-nucleotide human STING agonist. In syngeneic mouse tumor models, subcutaneous and oral MSA-2 regimens were well tolerated and stimulated interferon-β secretion in tumors, induced tumor regression with durable antitumor immunity, and synergized with anti–PD-1 therapy. Experimental and theoretical analyses showed that MSA-2 exists as interconverting monomers and dimers in solution, but only dimers bind and activate STING. This model was validated by using synthetic covalent MSA-2 dimers, which were potent agonists. Cellular potency of MSA-2 increased upon extracellular acidification, which mimics the tumor microenvironment. These properties appear to underpin the favorable activity and tolerability profiles of effective systemic administration of MSA-2.

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

“…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.…”

“…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.…”

Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system

“…In 2018, diABZI was discovered as a new class of synthetic small molecule STING receptor agonist with much higher potency than CDNs and suitable for systemic administration ( Ramanjulu et al, 2018 ). Recently, an orally available non-nucleotide STING agonist, MSA-2, was reported to have favorable activity and tolerability profiles ( Pan et al, 2020a ). Further optimization of these molecules for improved safety margins may still be needed for their clinical application against coronavirus infections.…”

From Phenotypic Hit to Chemical Probe: Chemical Biology Approaches to Elucidate Small Molecule Action in Complex Biological Systems

“…Alternatively, in cases where it is hard to predict the compound binding site, a library of compounds or fragments (see Section 2.3) can be screened against the purified protein target [12,13]. In some cases, the target is overexpressed in a cell system, or cells are engineered for a target-specific readout, blurring the line between target-based screening and phenotypic approaches as discussed below [14,15].…”

“…For example, phenotypic screens have been very powerful to identify compounds that inhibit cellular signaling pathways, such as Hedgehog [18], Wnt [19,20], STING [14], and NFκB [21] signaling. Signaling pathways are complex cellular protein networks essential for communication between cells, establishing, e.g., proper embryonic development, tissue homeostasis, and immune response, and much of the associated biology remains to be unraveled.…”