Discovery and optimization of 2,3-Dihydroindole derivatives as STING receptor allosteric agonists

Abstract

STING allosteric agonists targeting the cryptic pocket in the transmembrane domain (TMD) could overcome the limitations of membrane permeability and oligomerization instability that are inherent to conventional cGAMP mimetics. Although compounds such as C53 and NVS-STG2 have been reported as TMD-targeting agonists, their therapeutic potential is restricted by insufficient potency. In this work, compound LA24 was identified as a novel potent STING allosteric agonist through structure-based multilevel virtual screening combined with rational optimization. It exhibited an EC₅₀ value of 0.82 μM, being superior to that of the reference C53 (EC₅₀ = 2.80 μM). Molecular modeling studies revealed that LA24 exhibited enhanced STING agonistic activity by forming hydrogen bonds with key transmembrane domain residues G114 and Y106, as well as π–π stacking interactions with H50. These findings suggested that LA24 holds promise as a novel lead compound for the development of STING-targeted immunomodulatory therapies.