9FON

Cocrystal structure of Drosophila melanogaster TDO with a bound compound

This is a non-PDB format compatible entry.

Summary for 9FON

• Entry DOI: 10.2210/pdb9fon/pdb
• Descriptor: Tryptophan 2,3-dioxygenase, PROTOPORPHYRIN IX CONTAINING FE, (~{R})-(7-chloranylimidazo[1,5-a]pyridin-5-yl)-(1-phenyl-1,2,3-triazol-4-yl)methanol, ... (4 entities in total)
• Functional Keywords: inhibitor, heme, oxidoreductase
• Biological source: Drosophila melanogaster (fruit fly)
• Total number of polymer chains: 2
• Total formula weight: 88493.81

Authors

Wicki, M.,Mac Sweeney, A. (deposition date: 2024-06-12, release date: 2025-04-23, Last modification date: 2025-10-22)

Primary citation

Cren, S.,Lotz-Jenne, C.,Kimmerlin, T.,Pothier, J.,Risch, P.,Mac Sweeney, A.,Joesch, C.,Pouzol, L.,Chavanton-Arpel, A.,Boss, C.
Cellular Potency Optimization of Novel Heme-Binding Imidazo[5,1- b ]thiazoles, Imidazo[1,5- a ]pyridines and Pyrazines as Potent IDO1 Inhibitors Devoid of Cytochrome P450 Inhibition.
J.Med.Chem., 68:20130-20153, 2025

PubMed Abstract: Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) are key enzymes in the kynurenine pathway of the catabolism of the essential amino acid tryptophan. Both enzymes actively contribute to the immunosuppressive microenvironment in many types of cancer. Selective or dual inhibition of these enzymes could, therefore, be beneficial in combination with other immunotherapies such as immune-checkpoint therapy. In a fragment-based approach, we optimized fragment into a series of potent imidazo[5,1-]thiazole, imidazo[1,5-]pyridine and pyrazine IDO1 inhibitors. The introduction of the triazole side chain resulted in a reduced enzyme-to-cell potency shift for IDO1 inhibition, albeit at the expense of TDO2 potency, and allowed the discovery of potent and cellular active IDO1 inhibitors. Moreover, despite the propensity of the imidazole motif to inhibit cytochrome P450 enzymes (CYP), we were able to discover potent IDO1 inhibitors devoid of CYP inhibition. Imidazo[1,5-]pyrazine has an overall suitable profile, which warrants further investigation.

PubMed: 41002114
DOI: 10.1021/acs.jmedchem.5c01067

Experimental method

X-RAY DIFFRACTION (2.121 Å)