6WPE

HUMAN IDO1 IN COMPLEX WITH COMPOUND 4

Summary for 6WPE

• Entry DOI: 10.2210/pdb6wpe/pdb
• Descriptor: Indoleamine 2,3-dioxygenase 1, 4-chloro-N-{[1-(3-chlorobenzene-1-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]methyl}benzamide (3 entities in total)
• Functional Keywords: indoleamine dioxygenase, heme, inhibitor, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 89588.87

Authors

Lesburg, C.A.,Lammens, A. (deposition date: 2020-04-27, release date: 2021-03-10, Last modification date: 2024-10-16)

Primary citation

Li, D.,Deng, Y.,Achab, A.,Bharathan, I.,Hopkins, B.A.,Yu, W.,Zhang, H.,Sanyal, S.,Pu, Q.,Zhou, H.,Liu, K.,Lim, J.,Fradera, X.,Lesburg, C.A.,Lammens, A.,Martinot, T.A.,Cohen, R.D.,Doty, A.C.,Ferguson, H.,Nickbarg, E.B.,Cheng, M.,Spacciapoli, P.,Geda, P.,Song, X.,Smotrov, N.,Abeywickrema, P.,Andrews, C.,Chamberlin, C.,Mabrouk, O.,Curran, P.,Richards, M.,Saradjian, P.,Miller, J.R.,Knemeyer, I.,Otte, K.M.,Vincent, S.,Sciammetta, N.,Pasternak, A.,Bennett, D.J.,Han, Y.
Carbamate and N -Pyrimidine Mitigate Amide Hydrolysis: Structure-Based Drug Design of Tetrahydroquinoline IDO1 Inhibitors.
Acs Med.Chem.Lett., 12:389-396, 2021

PubMed Abstract: Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this class of compounds. Structure-based drug design and strategic incorporation of polarity enabled the rapid improvement on potency, solubility, and oxidative metabolic stability. Metabolite identification studies revealed that amide hydrolysis in the D-pocket was the key clearance mechanism for this class. Strategic survey of amide isosteres revealed that carbamates and -pyrimidines, which maintained exquisite potencies, mitigated the amide hydrolysis issue and led to an improved rat PK profile. The lead compound is a potent IDO1 inhibitor, with clean off-target profiles and the potential for quaque die dosing in humans.

PubMed: 33738066
DOI: 10.1021/acsmedchemlett.0c00525

Experimental method

X-RAY DIFFRACTION (2.43 Å)