6XF4

Crystal structure of STING REF variant in complex with E7766

Summary for 6XF4

• Entry DOI: 10.2210/pdb6xf4/pdb
• Descriptor: Stimulator of interferon genes protein, (1R,3R,15E,28R,29R,30R,31R,34R,36R,39S,41R)-29,41-difluoro-34,39-disulfanyl-2,33,35,38,40,42-hexaoxa-4,6,9,11,13,18,20,22,25,27-decaaza-34,39-diphosphaoctacyclo[28.6.4.1~3,36~.1~28,31~.0~4,8~.0~7,12~.0~19,24~.0~23,27~]dotetraconta-5,7,9,11,15,19,21,23,25-nonaene 34,39-dioxide (non-preferred name), 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: stimulator of interferon genes (sting), ref variant, e7766, agonist, macrocycle, immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 44281.43

Authors

Chen, Y.,Wang, J.Y.,Kim, D.-S. (deposition date: 2020-06-15, release date: 2021-02-17, Last modification date: 2024-04-03)

Primary citation

Kim, D.S.,Endo, A.,Fang, F.G.,Huang, K.C.,Bao, X.,Choi, H.W.,Majumder, U.,Shen, Y.Y.,Mathieu, S.,Zhu, X.,Sanders, K.,Noland, T.,Hao, M.H.,Chen, Y.,Wang, J.Y.,Yasui, S.,TenDyke, K.,Wu, J.,Ingersoll, C.,Loiacono, K.A.,Hutz, J.E.,Sarwar, N.
E7766, a Macrocycle-Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan-Genotypic Activity.
Chemmedchem, 16:1740-1743, 2021

PubMed 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.

PubMed: 33522135
DOI: 10.1002/cmdc.202100068

Experimental method

X-RAY DIFFRACTION (2.77 Å)