6WJY

HUMAN IDO1 IN COMPLEX WITH COMPOUND 4-A

Summary for 6WJY

• Entry DOI: 10.2210/pdb6wjy/pdb
• Descriptor: Indoleamine 2,3-dioxygenase 1, 3-chloro-N-(3-{(2S)-1-[(4-fluorophenyl)amino]-1-oxopropan-2-yl}bicyclo[1.1.1]pentan-1-yl)benzamide (3 entities in total)
• Functional Keywords: indoleamine dioxygenase, heme, inhibitor, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 89483.90

Authors

Lesburg, C.A.,Lammens, A.,Neumann, L. (deposition date: 2020-04-14, release date: 2020-08-26, Last modification date: 2024-11-06)

Primary citation

Pu, Q.,Zhang, H.,Guo, L.,Cheng, M.,Doty, A.C.,Ferguson, H.,Fradera, X.,Lesburg, C.A.,McGowan, M.A.,Miller, J.R.,Geda, P.,Song, X.,Otte, K.,Sciammetta, N.,Solban, N.,Yu, W.,Sloman, D.L.,Zhou, H.,Lammens, A.,Neumann, L.,Bennett, D.J.,Pasternak, A.,Han, Y.
Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors.
Acs Med.Chem.Lett., 11:1548-1554, 2020

PubMed Abstract: Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like have drawn considerable attention from both academia and the pharmaceutical industry. Here, we describe the discovery of a novel class of highly potent IDO1 heme-displacing inhibitors featuring a unique bicyclo[1.1.1]pentane motif. Compound , evolving from an ALIS (automated ligand identification system) hit, exhibited excellent potency but lacked the desired pharmacokinetic profile due to extensive amide hydrolysis of the benzamide moiety. Replacing the central phenyl ring in with a bicyclo[1.1.1]pentane bioisostere effectively circumvented the amide hydrolysis issue, resulting in the discovery of compound with a favorable overall profile such as excellent potency, selectivity, pharmacokinetics, and a low predicted human dose.

PubMed: 32832022
DOI: 10.1021/acsmedchemlett.0c00195

Experimental method

X-RAY DIFFRACTION (1.91 Å)