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 Jan 31;:
Authors: Kim DS, Endo A, Fang FG, Huang KC, Bao X, Choi HW, Majumder U, Shen YY, Mathieu S, Zhu X, Sanders K, Noland T, Hao MH, Chen Y, Wang JY, Yasui S, TenDyke K, Wu J, Ingersoll C, Loiacono KA, Hutz JE, Sarwar N
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 anti-tumor activity with long lasting immune memory response in a mouse liver metastatic tumor model. Two complementary stereoselective synthetic routes to E7766 are also described.
PMID: 33522135 [PubMed - as supplied by publisher]

Source: ChemMedChem - January 31, 2021 Category: Chemistry Authors: Kim DS, Endo A, Fang FG, Huang KC, Bao X, Choi HW, Majumder U, Shen YY, Mathieu S, Zhu X, Sanders K, Noland T, Hao MH, Chen Y, Wang JY, Yasui S, TenDyke K, Wu J, Ingersoll C, Loiacono KA, Hutz JE, Sarwar N Tags: ChemMedChem Source Type: research