6V52

IDO1 IN COMPLEX WITH COMPOUND 1

6V52 の概要

• エントリーDOI: 10.2210/pdb6v52/pdb
• 分子名称: Indoleamine 2,3-dioxygenase 1, 3-chloro-N-{4-[1-(propylcarbamoyl)cyclobutyl]phenyl}benzamide (3 entities in total)
• 機能のキーワード: indoleamine dioxygenase, heme, inhibitor, oxidoreductase
• 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: 89451.95

構造登録者

Lesburg, C.A.,Koenig, K.V.,Augustin, M.A. (登録日: 2019-12-03, 公開日: 2020-04-08, 最終更新日: 2024-11-20)

主引用文献

White, C.,McGowan, M.A.,Zhou, H.,Sciammetta, N.,Fradera, X.,Lim, J.,Joshi, E.M.,Andrews, C.,Nickbarg, E.B.,Cowley, P.,Trewick, S.,Augustin, M.,von Koenig, K.,Lesburg, C.A.,Otte, K.,Knemeyer, I.,Woo, H.,Yu, W.,Cheng, M.,Spacciapoli, P.,Geda, P.,Song, X.,Smotrov, N.,Curran, P.,Heo, M.R.,Abeywickrema, P.,Miller, J.R.,Bennett, D.J.,Han, Y.
Strategic Incorporation of Polarity in Heme-Displacing Inhibitors of Indoleamine-2,3-dioxygenase-1 (IDO1).
Acs Med.Chem.Lett., 11:550-557, 2020

PubMed Abstract: Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as a target of significant interest to the field of cancer immunotherapy, as the upregulation of IDO1 in certain cancers has been linked to host immune evasion and poor prognosis for patients. In particular, IDO1 inhibition is of interest as a combination therapy with immune checkpoint inhibition. Through an Automated Ligand Identification System (ALIS) screen, a diamide class of compounds was identified as a promising lead for the inhibition of IDO1. While hit possessed attractive cell-based potency, it suffered from a significant right-shift in a whole blood assay, poor solubility, and poor pharmacokinetic properties. Through a physicochemical property-based approach, including a focus on lowering AlogP via the strategic introduction of polar substitution, compound was identified bearing a pyridyl oxetane core. Compound demonstrated improved whole blood potency and solubility, and an improved pharmacokinetic profile resulting in a low predicted human dose.

PubMed: 32292563
DOI: 10.1021/acsmedchemlett.0c00010

実験手法

X-RAY DIFFRACTION (1.78 Å)