Discovery of a Novel and Selective Indoleamine 2,3-Dioxygenase (IDO-1) Inhibitor 3-(5-Fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (EOS200271/PF-06840003) and Its Characterization as a Potential Clinical Candidate

Abstract

Tumors use tryptophan-catabolizing enzymes such as indoleamine 2,3-dioxygenase (IDO-1) to induce an immunosuppressive environment. IDO-1 is induced in response to inflammatory stimuli and promotes immune tolerance through effector T-cell anergy and enhanced Treg function. As such, IDO-1 is a nexus for the induction of a key immunosuppressive mechanism and represents an important immunotherapeutic target in oncology. Starting from HTS hit 5, IDO-1 inhibitor 6 (EOS200271/PF-06840003) has been developed. The structure-activity relationship around 6 is described and rationalized using the X-ray crystal structure of 6 bound to human IDO-1, which shows that 6, differently from most of the IDO-1 inhibitors described so far, does not bind to the heme iron atom and has a novel binding mode. Clinical candidate 6 shows good potency in an IDO-1 human whole blood assay and also shows a very favorable ADME profile leading to favorable predicted human pharmacokinetic properties, including a predicted half-life of 16-19 h.

Characterization of the Selective Indoleamine 2,3-Dioxygenase-1 (IDO1) Catalytic Inhibitor EOS200271/PF-06840003 Supports IDO1 as a Critical Resistance Mechanism to PD-(L)1 Blockade Therapy

“…After incubation of pure PF-06840002 in plasma in vitro, a significant amount of PF-06840002 is converted to PF-06840001 in the first 6 hours in all of the three species tested ($65% in humans, 42% in dogs, and 34% in mice). Equilibration is achieved in 6 hours in humans, but delayed in dogs and mice (19). Based on this low interconversion barrier, the racemic mixture PF-06840003 rather than pure active enantiomer PF-06840002 was used in the in vivo experiments described below.…”

“…Exceptional selectivity for IDO1 and thus an overall low risk for off-target effects are further corroborated by CEREP-wide ligand profile and kinase panel screens. Although the IC 50 potency of the active enantiomer PF-06840002 in the enzymatic IDO1 assay does not reach the double-digit nanomolar range of the first described catalytic IDO1 inhibitor INCB024360 (17,30), low plasma protein binding ( Supplementary Table S1) coupled with favorable clearance and distribution characteristics provide a favorable human PK prediction for PF-06840002 (19).…”

New Insights from Crystallographic Data: Diversity of Structural Motifs and Molecular Recognition Properties between Groups of IDO1 Structures

“…5WHR‐A and ‐B, and 6F0A‐A and ‐C chains are outliers of group I chain structures of IDO1. In particular, 5WHR is the crystallographic dimeric structure of IDO1 in complex with the clinical candidate PF‐06840003 ( 10 ; Figure B) . This inhibitor is an analogue of l ‐Trp ( 1 ), with the succinimide moiety mimicking the aminoacidic group of the substrate and making hydrogen bonds with Thr379 and a propionate group of the heme cofactor.…”

“…Since the disclosure of the first crystal structure in 2006, applications of SBDD approaches to IDO1 have been fostered by the ever increasing number of entries in the PDB database (Figure ; Table S1 in the Supporting Information) . However, only few of these entries have hitherto been used for SBDD screening campaigns (33 %, Figure ) …”

Identification of novel imidazoles as IDO1 inhibitors through microwave‐assisted one‐pot multicomponent reactions

“…Currently, a Phase III clinical trial is evaluating BMS‐986205 in combination with nivolumab, developed by Bristol‐Myers Squibb Company . PF‐06840003 (IDO1 IC 50 = 410 nM), from Pfizer Inc./iTeos Therapeutics SA, is in Phase I clinical trials …”