Design, Synthesis, and Biological Evaluation of Bipyridazine Derivatives as Stimulator of Interferon Genes (STING) Receptor Agonists

Abstract

The development of stimulator of interferon genes (STING) agonists has been of potential applications for the treatment of cancer and infectious diseases. Based on the crystal structure of <b>SR-717</b> bound to hSTING, we designed and synthesized a novel series of bipyridazine derivatives as highly potent STING agonists. Among them, compound <b>12L</b> led to significant thermal stability shifts of the common alleles of hSTING, as well as that of mSTING. <b>12L</b> also displayed potent activities in various hSTING alleles and mSTING competition binding assay. Specifically, <b>12L</b> displayed higher cell-based activities than <b>SR-717</b> in both human THP1 (EC₅₀ = 0.38 ± 0.03 μM) and mouse RAW 264.7 cells (EC₅₀ = 12.94 ± 1.78 μM), and was validated to activate the downstream signaling pathway of STING via a STING-dependent manner. Furthermore, compound <b>12L</b> showed favorable pharmacokinetic (PK) properties and antitumor efficacy. These findings suggested that compound <b>12L</b> has development potential as an antitumor agent.