7RRB

IDO1 IN COMPLEX WITH COMPOUND 9

7RRB の概要

• エントリーDOI: 10.2210/pdb7rrb/pdb
• 分子名称: Indoleamine 2,3-dioxygenase 1, 3-[4-(6-cyclopropylpyridin-3-yl)phenyl]-N-(4-fluorophenyl)oxetane-3-carboxamide (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: 89487.07

構造登録者

Lesburg, C.A. (登録日: 2021-08-09, 公開日: 2022-03-16, 最終更新日: 2024-10-23)

主引用文献

Li, D.,Sloman, D.L.,Achab, A.,Zhou, H.,McGowan, M.A.,White, C.,Gibeau, C.,Zhang, H.,Pu, Q.,Bharathan, I.,Hopkins, B.,Liu, K.,Ferguson, H.,Fradera, X.,Lesburg, C.A.,Martinot, T.A.,Qi, J.,Song, Z.J.,Yin, J.,Zhang, H.,Song, L.,Wan, B.,DAddio, S.,Solban, N.,Miller, J.R.,Zamlynny, B.,Bass, A.,Freeland, E.,Ykoruk, B.,Hilliard, C.,Ferraro, J.,Zhai, J.,Knemeyer, I.,Otte, K.M.,Vincent, S.,Sciammetta, N.,Pasternak, A.,Bennett, D.J.,Han, Y.
Oxetane Promise Delivered: Discovery of Long-Acting IDO1 Inhibitors Suitable for Q3W Oral or Parenteral Dosing.
J.Med.Chem., 65:6001-6016, 2022

PubMed Abstract: 3,3-Disubstituted oxetanes have been utilized as bioisosteres for gem-dimethyl and cyclobutane functionalities. We report the discovery of a novel class of oxetane indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable for Q3W (once every 3 weeks) oral and parenteral dosing. A diamide class of IDO inhibitors was discovered through an automated ligand identification system (ALIS). Installation of an oxetane and fluorophenyl dramatically improved the potency. Identification of a biaryl moiety as an unconventional amide isostere addressed the metabolic liability of amide hydrolysis. Metabolism identification (Met-ID)-guided target design and the introduction of polarity resulted in the discovery of potent IDO inhibitors with excellent pharmacokinetic (PK) profiles in multiple species. To enable rapid synthesis of the key oxetane intermediate, a novel oxetane ring cyclization was also developed, as well as optimization of a literature route on kg scale. These IDO inhibitors may enable unambiguous proof-of-concept testing for the IDO1 inhibition mechanism for oncology.

PubMed: 35239336
DOI: 10.1021/acs.jmedchem.1c01670

実験手法

X-RAY DIFFRACTION (2.69 Å)