Azole-Based Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors

Abstract

The heme enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays an essential role in immunity, neuronal function, and aging through catalysis of the rate-limiting step in the kynurenine pathway of tryptophan metabolism. Many IDO1 inhibitors with different chemotypes have been developed, mainly targeted for use in anti-cancer immunotherapy. Lead optimization of direct heme iron-binding inhibitors has proven difficult due to the remarkable selectivity and sensitivity of the heme−ligand interactions. Here, we present experimental data for a set of closely related small azole compounds with more than 4 orders of magnitude differences in their inhibitory activities, ranging from millimolar to nanomolar levels. We investigate and rationalize their activities based on structural data, molecular dynamics simulations, and density functional theory calculations. Our results not only expand the presently known four confirmed chemotypes of sub-micromolar heme binding IDO1 inhibitors by two additional scaffolds but also provide a model to predict the activities of novel scaffolds.

Temporary Intermediates of L-Trp Along the Reaction Pathway of Human Indoleamine 2,3-Dioxygenase 1 and Identification of an Exo Site

“…[8][9][10] In particular, overexpression of hIDO1 by cancer cells has been shown to induce immune escape and resistance to immunotherapy [11][12][13][14] by decreasing T cell activation. 11,13,[15][16][17][18] Although more than 50 crystal structures exist for this therapeutic target, [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] only partial structures of the active site, that is, without the refinement of the dynamic JK-loop, were obtained so far. The JK-loop (residues 360-380) of hIDO1 is a dynamic loop located at the entrance of the active site, in contact with the heme cofactor.…”

Structure-based optimization of type III indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors

“…We have previously discovered 1,2,3-triazoles as highly efficient IDO1 inhibitors and resolved the X-ray structure of MMG-0358 ( 9 ) in complex with IDO1 ( Figure 1 ) 22 , 28 , 29 , 58 . Compound 9 forms a direct bond to the haem iron, a hydrogen bond with Ser167 through its hydroxy function, and hydrophobic interactions through its chloro substituent, leading to a LE of 0.76 kcal/mol/HA.…”

“…linrodostat) to apoIDO1. Lead optimisation of haem-iron binding type ii and type iii inhibitors has proven difficult due to the selectivity and sensitivity of the haem–ligand interactions to changes in the electronic structure of the ligand 28 and due to the small size of the distal haem pocket (pocket A) 29 , crucial for inhibitor activity. The IDO1 active site further comprises Pocket B, which extends from pocket A towards the entrance of the active site ( Figure 1B,C ), and whose size and shape are determined by the conformation of the flexible JK-loop 27 .…”

“…Early structure-based optimisation of this chemotype yielded the 2-hydroxy-substituted phenyl derivative as the most active compound 41 . Combination of the 2-hydroxy substitution with a 5-chloro substitution led to the most efficient imidazole compound ( 5 ) with a ligand efficiency (LE) of 0.68 kcal/mol/heavy atom (HA) 24 , 28 . In subsequent developments, extending the scaffold to pocket B, a drop in LE was always encountered 42 , but nanomolar activities could be obtained in some 1,5-disubstituted imidazoles 43 , 44 .…”

The [1,2,4]Triazolo[4,3‐a]pyridine as a New Player in the Field of IDO1 Catalytic Holo‐Inhibitors

“…In particular, among the iron-binding scaffolds with sub-micromolar potency, imidazoles (e. g. 4phenylimidazole), [36] hydroxyamidines (e. g. epacadostat), [37] indazoles, [38][39][40] and 1,2,3-triazoles [41] are the most exploited ones, while 1,2,4-triazole-based inhibitors are less represented and comprise Amg-1 (3, Figure 1), [42] a thiazolo [2,3-c] [1,2,4] triazole, and the recently reported 3-monosubstitued 1,2,4-triazole (4, Figure 1). [43] The under-representation of this substructure in the literature caught our attention and prompted us to start a medicinal chemistry campaign on VS9.…”