6PU7

Human IDO1 in complex with compound 17 (N-{2-[(4-{N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N'-hydroxycarbamimidoyl}-1,2,5-oxadiazol-3-yl)sulfanyl]ethyl}acetamide)

Summary for 6PU7

• Entry DOI: 10.2210/pdb6pu7/pdb
• Descriptor: Indoleamine 2,3-dioxygenase 1, PROTOPORPHYRIN IX CONTAINING FE, N-{2-[(4-{N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N'-hydroxycarbamimidoyl}-1,2,5-oxadiazol-3-yl)sulfanyl]ethyl}acetamide, ... (4 entities in total)
• Functional Keywords: indoleamine, dioxygenase, heme, inhibitor, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 90559.84

Authors

Lesburg, C.A. (deposition date: 2019-07-17, release date: 2019-12-04, Last modification date: 2024-10-23)

Primary citation

Zhang, H.,Liu, K.,Pu, Q.,Achab, A.,Ardolino, M.J.,Cheng, M.,Deng, Y.,Doty, A.C.,Ferguson, H.,Fradera, X.,Knemeyer, I.,Kurukulasuriya, R.,Lam, Y.H.,Lesburg, C.A.,Martinot, T.A.,McGowan, M.A.,Miller, J.R.,Otte, K.,Biju, P.J.,Sciammetta, N.,Solban, N.,Yu, W.,Zhou, H.,Wang, X.,Bennett, D.J.,Han, Y.
Discovery of Amino-cyclobutarene-derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors for Cancer Immunotherapy.
Acs Med.Chem.Lett., 10:1530-1536, 2019

PubMed Abstract: Checkpoint inhibitors have demonstrated unprecedented efficacy and are evolving to become standard of care for certain types of cancers. However, low overall response rates often hamper the broad utility and potential of these breakthrough therapies. Combination therapy strategies are currently under intensive investigation in the clinic, including the combination of PD-1/PD-L1 agents with IDO1 inhibitors. Here, we report the discovery of a class of IDO1 heme-binding inhibitors featuring a unique amino-cyclobutarene motif, which was discovered through SBDD from a known and weakly active inhibitor. Subsequent optimization efforts focused on improving metabolic stability and were greatly accelerated by utilizing a robust SAr reaction of a facile nitro-furazan intermediate to quickly explore different polar side chains. As a culmination of these efforts, compound was identified and demonstrated a favorable overall profile with superior potency and selectivity. Extensive studies confirmed the chemical stability and drug-like properties of compound , rendering it a potential drug candidate.

PubMed: 31749906
DOI: 10.1021/acsmedchemlett.9b00344

Experimental method

X-RAY DIFFRACTION (2.43 Å)