Design, Synthesis, and Biological Evaluation of Bipyridazine Derivatives as Stimulator of Interferon Genes (STING) Receptor Agonists
Bin Shan, Hui Hou, Keke Zhang, Rui Li, Chang Shen, Zhengyang Chen, Peijia Xu, Rongrong Cui, Zhaoming Su, Changfa Zhang, Ruirui Yang, Guizhen Zhou, Yadan Liu, Hao Guo, Kaixian Chen, Wei Fu, Hualiang Jiang, Sulin Zhang, Mingyue Zheng
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 SR-717 bound to hSTING, we designed and synthesized a novel series of bipyridazine derivatives as highly potent STING agonists. Among them, compound 12L led to significant thermal stability shifts of the common alleles of hSTING, as well as that of mSTING. 12L also displayed potent activities in various hSTING alleles and mSTING competition binding assay. Specifically, 12L displayed higher cell-based activities than SR-717 in both human THP1 (EC 50 = 0.38 ± 0.03 μM) and mouse RAW 264.7 cells (EC 50 = 12.94 ± 1.78 μM), and was validated to activate the downstream signaling pathway of STING via a STING-dependent manner. Furthermore, compound 12L showed favorable pharmacokinetic (PK) properties and antitumor efficacy. These findings suggested that compound 12L has development potential as an antitumor agent.