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

  • ChemMedChem. 2021 Jun 7;16(11):1740-1743. doi: 10.1002/cmdc.202100068.
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
  • 1. Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA.
  • 2. H3 Biomedicine, 300 Technology Square FL5, Cambridge, MA 02139, USA.
  • 3. Analytical Research Laboratories, Pharmaceutical Science & Technology, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki, 300-2635, Japan.
PMID: 33522135 DOI: 10.1002/cmdc.202100068
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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