8FUR

Crystal structure of human IDO1 with compound 11

Summary for 8FUR

• Entry DOI: 10.2210/pdb8fur/pdb
• Descriptor: Indoleamine 2,3-dioxygenase 1, N-(4-methylphenyl)-N'-[(1P,2'P)-4-propoxy-5-propyl-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-3-yl]urea (3 entities in total)
• Functional Keywords: indoleamine-2, 3-dioxygenase, tryptophan catabolism, kynurenine, oxidoreductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 184548.18

Authors

Critton, D.A.,Lewis, H.A. (deposition date: 2023-01-18, release date: 2023-04-26, Last modification date: 2024-11-13)

Primary citation

Markwalder, J.A.,Balog, A.J.,Williams, D.K.,Nara, S.J.,Reddy, R.,Roy, S.,Kanyaboina, Y.,Li, X.,Johnston, K.,Fan, Y.,Lewis, H.,Marsilio, F.,Yan, C.,Critton, D.,Newitt, J.A.,Traeger, S.C.,Wu, D.R.,Jure-Kunkel, M.N.,Jayaraman, L.,Lin, T.A.,Sinz, M.W.,Hunt, J.T.,Seitz, S.P.
Synthesis and biological evaluation of biaryl alkyl ethers as inhibitors of IDO1.
Bioorg.Med.Chem.Lett., 88:129280-129280, 2023

PubMed Abstract: Starting from the dialkylaniline indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor lead 3 (IDO1 HeLa IC = 7.0 nM), an iterative process of synthesis and screening led to cyclized analog 21 (IDO1 HeLa IC = 3.6 nM) which maintained the high potency of 3 while addressing issues of lipophilicity, cytochrome P450 (CYP) inhibition, hERG (human potassium ion channel Kv11.1) inhibition, Pregnane X Receptor (PXR) transactivation, and oxidative metabolic stability. An x-ray crystal structure of a biaryl alkyl ether 11 bound to IDO1 was obtained. Consistent with our earlier results, compound 11 was shown to bind to the apo form of the enzyme.

PubMed: 37054759
DOI: 10.1016/j.bmcl.2023.129280

Experimental method

X-RAY DIFFRACTION (2.285 Å)