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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.

Original publication

DOI

10.1021/acs.jmedchem.7b00974

Type

Journal article

Journal

J Med Chem

Publication Date

14/12/2017

Volume

60

Pages

9617 - 9629

Keywords

Animals, Cell Line, Crystallography, X-Ray, Dogs, Enzyme Inhibitors, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, Indoles, Macaca fascicularis, Male, Mice, Molecular Docking Simulation, Rats, Structure-Activity Relationship, Succinimides