An orally available non-nucleotide STING agonist with antitumor activity

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.

Source: ScienceNOW - August 19, 2020 Category: Science Authors: Pan, B.-S., Perera, S. A., Piesvaux, J. A., Presland, J. P., Schroeder, G. K., Cumming, J. N., Trotter, B. W., Altman, M. D., Buevich, A. V., Cash, B., Cemerski, S., Chang, W., Chen, Y., Dandliker, P. J., Feng, G., Haidle, A., Henderson, T., Jewell, J., K Tags: Medicine, Diseases, Online Only r-articles Source Type: news