2. Academic Validation
  3. E7766, a Macrocycle-Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan-Genotypic Activity

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

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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