Identification of MSA-2: An oral antitumor non-nucleotide STING agonist
Jianhua Liu, Xu Huang, Jianxun Ding
Abstract
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 ). Fig. 1 Through high-throughput screening, MSA-2 was identified as a promising STING agonist from ~2.4 million compounds. Only pre-dimerized MSA-2 could bind to STING. In the acidic tumor microenvironment, uncharged MSA-2 showed a higher permeable ability and thus preferentially activated STING compared to normal tissues. Oral administration of MSA-2 exhibited excellent safety tolerance and synergetic antitumor effects with anti-PD-1 therapy in vivo Full size image