An orally available non-nucleotide STING agonist with antitumor activity.
Bo-Sheng PanSamanthi A PereraJennifer A PiesvauxJeremy P PreslandGottfried K SchroederJared N CummingBenjamin Wesley TrotterMichael D AltmanAlexei V BuevichBrandon CashSaso CemerskiWonsuk ChangYiping ChenPeter J DandlikerGuo FengAndrew M HaidleTimothy HendersonJames JewellIlona KarivIan KnemeyerJohnny E KopinjaBrian M LaceyJason LaskeyCharles A LesburgRui LiangBrian J LongMin LuYanhong MaEllen C MinnihanGreg O'DonnellRyan OtteLaura PriceLarissa RakhilinaBerengere SauvagnatSharad K SharmaSriram TyagarajanHyun WooDaniel F WyssSerena XuDavid Jonathan BennettGeorge H AddonaPublished in: Science (New York, N.Y.) (2020)
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.