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E7766, a Macrocycle-Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan-Genotypic Activity |
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| Authors: | Dr Dae-Shik Kim Dr Atsushi Endo Dr Francis G Fang Dr Kuan-Chun Huang Dr Xingfeng Bao Dr Hyeong-wook Choi Dr Utpal Majumder Dr Young Y Shen Steven Mathieu Xiaojie Zhu Kristen Sanders Dr Thomas Noland Dr Ming-Hong Hao Dr Yu Chen Dr John Y Wang So Yasui Karen TenDyke Jiayi Wu Christy Ingersoll Kara A Loiacono Dr Janna E Hutz Dr Nadeem Sarwar |
| Affiliation: | 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 |
| 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: | cyclic dinucleotides drug design immuno-oncology macrocycles STING agonists |
