6PU7

Human IDO1 in complex with compound 17 (N-{2-[(4-{N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N'-hydroxycarbamimidoyl}-1,2,5-oxadiazol-3-yl)sulfanyl]ethyl}acetamide)

6PU7 の概要

• エントリーDOI: 10.2210/pdb6pu7/pdb
• 分子名称: Indoleamine 2,3-dioxygenase 1, PROTOPORPHYRIN IX CONTAINING FE, N-{2-[(4-{N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N'-hydroxycarbamimidoyl}-1,2,5-oxadiazol-3-yl)sulfanyl]ethyl}acetamide, ... (4 entities in total)
• 機能のキーワード: indoleamine, dioxygenase, heme, inhibitor, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 90559.84

構造登録者

Lesburg, C.A. (登録日: 2019-07-17, 公開日: 2019-12-04, 最終更新日: 2024-10-23)

主引用文献

Zhang, H.,Liu, K.,Pu, Q.,Achab, A.,Ardolino, M.J.,Cheng, M.,Deng, Y.,Doty, A.C.,Ferguson, H.,Fradera, X.,Knemeyer, I.,Kurukulasuriya, R.,Lam, Y.H.,Lesburg, C.A.,Martinot, T.A.,McGowan, M.A.,Miller, J.R.,Otte, K.,Biju, P.J.,Sciammetta, N.,Solban, N.,Yu, W.,Zhou, H.,Wang, X.,Bennett, D.J.,Han, Y.
Discovery of Amino-cyclobutarene-derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors for Cancer Immunotherapy.
Acs Med.Chem.Lett., 10:1530-1536, 2019

PubMed Abstract: Checkpoint inhibitors have demonstrated unprecedented efficacy and are evolving to become standard of care for certain types of cancers. However, low overall response rates often hamper the broad utility and potential of these breakthrough therapies. Combination therapy strategies are currently under intensive investigation in the clinic, including the combination of PD-1/PD-L1 agents with IDO1 inhibitors. Here, we report the discovery of a class of IDO1 heme-binding inhibitors featuring a unique amino-cyclobutarene motif, which was discovered through SBDD from a known and weakly active inhibitor. Subsequent optimization efforts focused on improving metabolic stability and were greatly accelerated by utilizing a robust SAr reaction of a facile nitro-furazan intermediate to quickly explore different polar side chains. As a culmination of these efforts, compound was identified and demonstrated a favorable overall profile with superior potency and selectivity. Extensive studies confirmed the chemical stability and drug-like properties of compound , rendering it a potential drug candidate.

PubMed: 31749906
DOI: 10.1021/acsmedchemlett.9b00344

実験手法

X-RAY DIFFRACTION (2.43 Å)