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. 2021 Jun 7;16(11):1740-1743.
doi: 10.1002/cmdc.202100068. Epub 2021 Feb 25.

E7766, a Macrocycle-Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan-Genotypic Activity

Dae-Shik Kim  1 , Atsushi Endo  1 , Francis G Fang  1 , Kuan-Chun Huang  2 , Xingfeng Bao  2 , Hyeong-Wook Choi  1 , Utpal Majumder  1 , Young Y Shen  1 , Steven Mathieu  1 , Xiaojie Zhu  1 , Kristen Sanders  1 , Thomas Noland  1 , Ming-Hong Hao  1 , Yu Chen  1 , John Y Wang  1 , So Yasui  3 , Karen TenDyke  1 , Jiayi Wu  2 , Christy Ingersoll  1 , Kara A Loiacono  1 , Janna E Hutz  1 , Nadeem Sarwar  1
Affiliations

E7766, a Macrocycle-Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan-Genotypic Activity

Dae-Shik Kim et al. ChemMedChem. .

Abstract

A strategy for creating potent and pan-genotypic stimulator of interferon genes (STING) agonists is described. Locking a bioactive U-shaped conformation of cyclic dinucleotides by introducing a transannular macrocyclic bridge between the nucleic acid bases leads to a topologically novel macrocycle-bridged STING agonist (MBSA). In addition to substantially enhanced potency, the newly designed MBSAs, exemplified by clinical candidate E7766, exhibit broad pan-genotypic activity in all major human STING variants. E7766 is shown to have potent antitumor activity with long lasting immune memory response in a mouse liver metastatic tumor model. Two complementary stereoselective synthetic routes to E7766 are also described.

Keywords: STING agonists; cyclic dinucleotides; drug design; immuno-oncology; macrocycles.

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