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

Autor: Kim DS; Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA., Endo A; Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA., Fang FG; Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA., Huang KC; H3 Biomedicine, 300 Technology Square FL5, Cambridge, MA 02139, USA., Bao X; H3 Biomedicine, 300 Technology Square FL5, Cambridge, MA 02139, USA., Choi HW; Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA., Majumder U; Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA., Shen YY; Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA., Mathieu S; Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA., Zhu X; Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA., Sanders K; Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA., Noland T; Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA., Hao MH; Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA., Chen Y; Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA., Wang JY; Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA., Yasui S; Analytical Research Laboratories, Pharmaceutical Science & Technology, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki, 300-2635, Japan., TenDyke K; Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA., Wu J; H3 Biomedicine, 300 Technology Square FL5, Cambridge, MA 02139, USA., Ingersoll C; Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA., Loiacono KA; Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA., Hutz JE; Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA., Sarwar N; Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2021 Jun 07; Vol. 16 (11), pp. 1740-1743. Date of Electronic Publication: 2021 Feb 25.
DOI: 10.1002/cmdc.202100068
Abstrakt: 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.
(© 2021 Wiley-VCH GmbH.)
Databáze: MEDLINE
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