methyl-thiohydantoin-tryptophan and Neoplasms

Indoleamine 2,3-dioxygenase 1 (IDO1), a known immunosuppressive enzyme that catalyzes the rate-limiting step in the oxidation of tryptophan (Trp) to kynurenine (Kyn), has received increasing attention as an attractive immunotherapeutic target for cancer therapy. Up to now, eleven small-molecule IDO1 inhibitors have entered clinical trials for the treatment of cancers. In addition, proteolysis targeting chimera (PROTAC) based degraders also provide prospects for cancer therapy. Herein we present a comprehensive overview of the medicinal chemistry strategies and potential therapeutic applications of IDO1 inhibitors in nonclinical trials and IDO1-PROTAC degraders.

Topics: Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Molecular Structure; Neoplasms; Proteolysis; Small Molecule Libraries

The enzyme indoleamine 2,3-dioxygenase (IDO) regulates immune responses through the capacity to degrade the essential amino acid tryptophan into kynurenine and other downstream metabolites that suppress effector T-cell function and favour the differentiation of regulatory T cells. Considerable experimental evidence indicates that IDO can be expressed by dendritic cells, by tumour cells or by surrounding stromal cells, either within proximity of the tumour or at distal sites. Recent advances in the biochemistry of IDO and in our understanding of the biological relevance of IDO-mediated tryptophan consumption to the establishment of dominant immune tolerance to cancer will be summarised and discussed. Within the wider context of cancer immunotherapy, this Review also delineates how IDO could be exploited as a molecular target for therapeutic intervention in order to boost anti-cancer immunity.

Topics: Animals; Antigens, CD; Binding Sites; CTLA-4 Antigen; Cyclooxygenase 2; Enzyme Inhibitors; Humans; Immune Tolerance; Indoleamine-Pyrrole 2,3,-Dioxygenase; Indoles; Interferon-gamma; Interleukin-2 Receptor alpha Subunit; Neoplasms; Thiohydantoins