molecules of the month


oral non-nucleoside STING agonist

single agent systemic activity in I/O model

from 2.4M cmpd cell-based phenotypic screen

Science, Aug. 21, 2020

Merck & Co., Kenilworth, NJ

Structure of non-nucleotide STING agonist MSA-2
1 min read

MSA-2 is an orally available agonist of the STING protein, which potently induces inflammation. Clinically evaluated cyclic dinucleotide-based STING agonists have typically been dosed intratumorally to promote anti-tumor inflammation but avoid systemic inflammation. The compound binds in a 2:1 stoichiometry with STING, and forcibly dimerized versions of MSA-2 are significantly more potent against STING. Interestingly, the compound demonstrates oral activity in cancer immunotherapy models at well-tolerated concentrations. The apparent tumor selectivity is hypothesized to be due to the weakly acidic nature of molecule. The mildly acidic tumor microenvironment favors the more permeable, protonated form of MSA-2, which can accumulate within the more basic tumor cells through a sink effect.

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