8P01

Crystal structure of human STING ectodomain in complex with BI 7446, a potent cyclic dinucleotide STING agonist with broad-spectrum variant activity for the treatment of cancer

8P01 の概要

• エントリーDOI: 10.2210/pdb8p01/pdb
• 分子名称: Stimulator of interferon genes protein, 3-[(1~{R},3~{R},6~{R},8~{R},9~{R},10~{R},12~{R},15~{R},17~{R},18~{R})-8-(6-aminopurin-9-yl)-9-fluoranyl-18-oxidanyl-3,12-bis(oxidanylidene)-3,12-bis(sulfanyl)-2,4,7,11,13,16-hexaoxa-3$l^{5},12$l^{5}-diphosphatricyclo[13.2.1.0^{6,10}]octadecan-17-yl]-6~{H}-imidazo[4,5-d]pyridazin-7-one (3 entities in total)
• 機能のキーワード: agonist, complex, innate immune response, immune system
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29037.33

構造登録者

Nar, H. (登録日: 2023-05-09, 公開日: 2023-07-26, 最終更新日: 2024-06-19)

主引用文献

Kuttruff, C.A.,Fleck, M.,Carotta, S.,Arnhof, H.,Bretschneider, T.,Dahmann, G.,Gremel, G.,Grube, A.,Handschuh, S.,Heimann, A.,Hofmann, M.H.,Impagnatiello, M.A.,Nar, H.,Rast, G.,Schaaf, O.,Schmidt, E.,Oost, T.
Discovery of BI 7446: A Potent Cyclic Dinucleotide STING Agonist with Broad-Spectrum Variant Activity for the Treatment of Cancer.
J.Med.Chem., 66:9376-9400, 2023

PubMed Abstract: Activating the stimulator of interferon genes (STING) pathway with STING agonists is an attractive immune oncology concept to treat patients with tumors that are refractory to single-agent anti-PD-1 therapy. For best clinical translatability and broad application to cancer patients, STING agonists with potent cellular activation of all STING variants are desired. Novel cyclic dinucleotide (CDN)-based selective STING agonists were designed and synthesized comprising noncanonical nucleobase, ribose, and phosphorothioate moieties. This strategy led to the discovery of 2',3'-CDN (BI 7446), which features unprecedented potency and activates all five STING variants in cellular assays. ADME profiling revealed that CDN has attractive drug-like properties for development as an intratumoral agent. Injection of low doses of CDN into tumors in mice induced long-lasting, tumor-specific immune-mediated tumor rejection. Based on its compelling preclinical profile, BI 7446 has been advanced to clinical trials (monotherapy and in combination with anti-PD-1 antibody).

PubMed: 37450324
DOI: 10.1021/acs.jmedchem.3c00510

実験手法

X-RAY DIFFRACTION (2.094 Å)