indoximod 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

Indoleamine 2, 3-dioxygenase 1 (IDO1) is a rate-limiting enzyme that catalyzes the kynurenine (Kyn) pathway of tryptophan metabolism in the first step, and the kynurenine pathway plays a fundamental role in immunosuppression in the tumor microenvironment. Therefore, researchers are vigorously developing IDO1 inhibitors, hoping to apply them to cancer immunotherapy. Nowadays, there have been 11 kinds of IDO1 inhibitors entering clinical trials, among which many inhibitors have shown good tumor inhibitory effect in phase I/II clinical trials. But the phase III study of the most promising IDO1 inhibitor compound 29 (Epacadostat) failed in 2018, which may be caused by the compensation effect offered by tryptophan 2,3-dioxygenase (TDO), the mismatched drug combination strategies, or other reasons. Luckily, dual-target inhibitors show great potential and advantages in solving these problems. In recent years, many studies have linked IDO1 to popular targets and selected many IDO1 dual-target inhibitors through pharmacophore fusion strategy and library construction, which enhance the tumor inhibitory effect and reduce side effects. Currently, three kinds of IDO1/TDO dual-target inhibitors have entered clinical trials, and extensive studies have been developing on IDO1 dual-target inhibitors. In this review, we summarize the IDO1 dual-target inhibitors developed in recent years and focus on the structure optimization process, structure-activity relationship, and the efficacy of in vitro and in vivo experiments, shedding a light on the pivotal significance of IDO1 dual-target inhibitors in the treatment of cancer, providing inspiration for the development of new IDO1 dual-target inhibitors.

Topics: Enzyme Inhibitors; Humans; Immunotherapy; Indoleamine-Pyrrole 2,3,-Dioxygenase; Kynurenine; Neoplasms; Tryptophan Oxygenase; Tumor Microenvironment

Indoleamine 2,3-dioxygenase 1 (IDO1) has received increasing attention due to its immunosuppressive function in connection with various diseases, including cancer. A recent increase in the understanding of IDO1 has significantly contributed to the discovery of numerous novel inhibitors, but the latest clinical outcomes raised questions and have indicated a future direction of IDO1 inhibition for therapeutic approaches. Herein, we present a comprehensive review of IDO1, discussing the latest advances in understanding the IDO1 structure and mechanism, an overview of recent IDO1 inhibitor discoveries and potential therapeutic applications to provide helpful information for medicinal chemists investigating IDO1 inhibitors.

Topics: Binding Sites; Catalytic Domain; Drug Discovery; Enzyme Inhibitors; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Indoles; Molecular Docking Simulation; Neoplasms; Small Molecule Libraries

There has been great attention on indoleamine-2,3-dioxygenase 1 (IDO1) around cancer immunotherapy because of its role in enabling cancers to evade the immune system. The most recent spurt of high potent IDO1 inhibitors has been driven by the solution of the increased crystal structures of inhibitors with IDO1. Though the structural information of the active site of IDO1 obtained from the crystals are quite similar, the structures of reported potent inhibitors are quite different. Besides, while thousands of bioactive small molecule inhibitors of IDO1 exist, to date, only five compounds have entered clinical trials. In an effort to obtain more clinical drugs targeting IDO1, more comprehensive understanding of the active site of IDO1 and the structures of existing potent IDO1 inhibitors are necessary. Thus, this review mainly focus on the key features reported from specific crystal structures of IDO1 and an overview of the most recently developed IDO1 inhibitors under investigation and their other derived applications which may contribute to a better usage in cancer immunotherapy.

Topics: Dose-Response Relationship, Drug; Drug Discovery; Enzyme Inhibitors; Humans; Immunotherapy; Indoleamine-Pyrrole 2,3,-Dioxygenase; Molecular Structure; Neoplasms; Structure-Activity Relationship

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Movement; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors; G2 Phase Cell Cycle Checkpoints; HeLa Cells; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Kynurenine; Male; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Reactive Oxygen Species; T-Lymphocytes; Tubulin Modulators; Xenograft Model Antitumor Assays

A series of different prodrugs of indoximod, including estesrs and peptide amides were synthesized with the aim of improving its oral bioavailability in humans. The pharmacokinetics of prodrugs that were stable in buffers, plasma and simulated gastric and intestinal fluids was first assessed in rats after oral dosing in solution or in capsule formulation. Two prodrugs that produced the highest exposure to indoximod in rats were further tested in Cynomolgus monkeys, a species in which indoximod has oral bioavailability of 6-10% and an equivalent dose-dependent exposure profile as humans. NLG802 was selected as the clinical development candidate after increasing oral bioavailability (>5-fold), C

Topics: Administration, Oral; Animals; Antineoplastic Agents; Apoptosis; Biological Availability; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Compounding; Drug Screening Assays, Antitumor; Haplorhini; Humans; Intestinal Absorption; Mice; Molecular Conformation; Neoplasms; Prodrugs; Rats; Tryptophan