6V52

IDO1 IN COMPLEX WITH COMPOUND 1

Summary for 6V52

• Entry DOI: 10.2210/pdb6v52/pdb
• Descriptor: Indoleamine 2,3-dioxygenase 1, 3-chloro-N-{4-[1-(propylcarbamoyl)cyclobutyl]phenyl}benzamide (3 entities in total)
• Functional Keywords: indoleamine dioxygenase, heme, inhibitor, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 89451.95

Authors

Lesburg, C.A.,Koenig, K.V.,Augustin, M.A. (deposition date: 2019-12-03, release date: 2020-04-08, Last modification date: 2024-11-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.78 Å)