Drugging large protein pockets is a challenge due to the need for higher molecular weight ligands which generally possess undesirable physicochemical properties. In this communication, we highlight a strategy utilizing dimeric small molecule binding to inhibit the STING protein, which contains a large symmetric binding site. By taking advantage of the 2:1 binding stoichiometry, maximal buried interaction with STING protein can be achieved while maintaining the ligand physicochemical properties necessary for oral exposure. This mode of binding requires unique considerations for potency optimization including simultaneous optimization of protein-ligand as well as ligand-ligand interactions. Successful implementation of this strategy led to the identification of a lead compound, which exhibits good oral exposure, slow binding kinetics, and functional inhibition of STING mediated cytokine release.

Discovery of small molecule STING antagonists: Novel use of small molecule dimers to drug large protein pockets

2019 Fall National Meeting

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