6ul0
STING C-terminal Domain Complexed with Non-cyclic Dinucleotide Compound 4STING C-terminal Domain Complexed with Non-cyclic Dinucleotide Compound 4
Structural highlights
Function[SMT3_YEAST] Not known; suppressor of MIF2 mutations. Publication Abstract from PubMedPharmacological 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-beta 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. An orally available non-nucleotide STING agonist with antitumor activity.,Pan BS, Perera SA, Piesvaux JA, Presland JP, Schroeder GK, Cumming JN, Trotter BW, Altman MD, Buevich AV, Cash B, Cemerski S, Chang W, Chen Y, Dandliker PJ, Feng G, Haidle A, Henderson T, Jewell J, Kariv I, Knemeyer I, Kopinja J, Lacey BM, Laskey J, Lesburg CA, Liang R, Long BJ, Lu M, Ma Y, Minnihan EC, O'Donnell G, Otte R, Price L, Rakhilina L, Sauvagnat B, Sharma S, Tyagarajan S, Woo H, Wyss DF, Xu S, Bennett DJ, Addona GH Science. 2020 Aug 21;369(6506). pii: 369/6506/eaba6098. doi:, 10.1126/science.aba6098. PMID:32820094[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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