Browse
Submit Data
Databases
API
Help

Dataset Information

24 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors in clinical trials for cancer immunotherapy.

ABSTRACT: Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme enzyme that catalyzes the oxidation of L-tryptophan. Functionally, IDO1 has played a pivotal role in cancer immune escape via catalyzing the initial step of the kynurenine pathway, and overexpression of IDO1 is also associated with poor prognosis in various cancers. Currently, several small-molecule candidates and peptide vaccines are currently being assessed in clinical trials. Furthermore, the "proteolysis targeting chimera" (PROTAC) technology has also been successfully used in the development of IDO1 degraders, providing novel therapeutics for cancers. Herein, we review the biological functions of IDO1, structural biology and also extensively summarize medicinal chemistry strategies for the development of IDO1 inhibitors in clinical trials. The emerging PROTAC-based IDO1 degraders are also highlighted. This review may provide a comprehensive and updated overview on IDO1 inhibitors and their therapeutic potentials.

SUBMITTER: Tang K

PROVIDER: S-EPMC8061021 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Discovery of Amino-cyclobutarene-derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors for Cancer Immunotherapy.

Project description:Checkpoint inhibitors have demonstrated unprecedented efficacy and are evolving to become standard of care for certain types of cancers. However, low overall response rates often hamper the broad utility and potential of these breakthrough therapies. Combination therapy strategies are currently under intensive investigation in the clinic, including the combination of PD-1/PD-L1 agents with IDO1 inhibitors. Here, we report the discovery of a class of IDO1 heme-binding inhibitors featuring a unique amino-cyclobutarene motif, which was discovered through SBDD from a known and weakly active inhibitor. Subsequent optimization efforts focused on improving metabolic stability and were greatly accelerated by utilizing a robust SNAr reaction of a facile nitro-furazan intermediate to quickly explore different polar side chains. As a culmination of these efforts, compound 16 was identified and demonstrated a favorable overall profile with superior potency and selectivity. Extensive studies confirmed the chemical stability and drug-like properties of compound 16, rendering it a potential drug candidate.

| S-EPMC6862341 | biostudies-literature

Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl hydrocarbon receptor.

Project description:Indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role in the immune system by regulating tryptophan levels and T cell differentiation. Several tumor types overexpress IDO1 to avoid immune surveillance making IDO1 of interest as a target for therapeutic intervention. As a result, several IDO1 inhibitors are currently being tested in clinical trials for cancer treatment as well as several other diseases. Many of the IDO1 inhibitors in clinical trials naturally bear structural similarities to the IDO1 substrate tryptophan, as such, they fulfill many of the structural and functional criteria as potential AHR ligands. Using mouse and human cell-based luciferase gene reporter assays, qPCR confirmation experiments, and CYP1A1 enzyme activity assays, we report that some of the promising clinical IDO1 inhibitors also act as agonists for the aryl hydrocarbon receptor (AHR), best known for its roles in xenobiotic metabolism and as another key regulator of the immune response. The dual role as IDO antagonist and AHR agonist for many of these IDO target drugs should be considered for full interrogation of their biological mechanisms and clinical outcomes.

| S-EPMC5495139 | biostudies-literature

Recent advances in the discovery of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors.

Project description:Indoleamine 2,3-dioxygenase 1 (IDO1), an important immunoregulatory enzyme ubiquitously expressed in various tissues and cells, plays a key role in tryptophan metabolism via the kynurenine pathway and has emerged as an attractive therapeutic target for the treatment of cancer and other diseases, such as Alzheimer's disease and arthritis. IDO1 has diverse biological roles in immune suppression and tumor progression by tryptophan catabolism. In addition, IDO1-mediated immune tolerance assists tumor cells in escaping the immune surveillance. Recently, extensive and enormous investigations have been made in the discovery of IDO1 inhibitors in both academia and pharmaceutical companies. In this review, IDO1 inhibitors are grouped as tryptophan derivatives, inhibitors with an imidazole, 1,2,3-triazole or tetrazole scaffold, inhibitors with quinone or iminoquinone, N-hydroxyamidines and other derivatives, and their enzymatic inhibitory activity, selectivity and other biological activities are also introduced and summarized.

| S-EPMC7003884 | biostudies-literature

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

Project description:The haem enzyme indoleamine 2,3-dioxygenase 1 (IDO1) catalyses the rate-limiting step in the kynurenine pathway of tryptophan metabolism and plays an essential role in immunity, neuronal function, and ageing. Expression of IDO1 in cancer cells results in the suppression of an immune response, and therefore IDO1 inhibitors have been developed for use in anti-cancer immunotherapy. Here, we report an extension of our previously described highly efficient haem-binding 1,2,3-triazole and 1,2,4-triazole inhibitor series, the best compound having both enzymatic and cellular IC50 values of 34 nM. We provide enzymatic inhibition data for almost 100 new compounds and X-ray diffraction data for one compound in complex with IDO1. Structural and computational studies explain the dramatic drop in activity upon extension to pocket B, which has been observed in diverse haem-binding inhibitor scaffolds. Our data provides important insights for future IDO1 inhibitor design.

| S-EPMC9246256 | biostudies-literature

Identification of Potent Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors Based on a Phenylimidazole Scaffold.

Project description:Inhibition of indoleamine 2,3-dioxygenase (IDO1) is an attractive immunotherapeutic approach for the treatment of a variety of cancers. Dysregulation of this enzyme has also been implicated in other disorders including Alzheimer's disease and arthritis. Herein, we report the structure-based design of two related series of molecules: N1-substituted 5-indoleimidazoles and N1-substituted 5-phenylimidazoles. The latter (and more potent) series was accessed through an unexpected rearrangement of an imine intermediate during a Van Leusen imidazole synthesis reaction. Evidence for the binding modes for both inhibitor series is supported by computational and structure-activity relationship studies.

| S-EPMC5807880 | biostudies-literature

Discovery of Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) and Histone Deacetylase (HDAC) Dual Inhibitors.

Project description:In order to take advantage of both immunotherapeutic and epigenetic antitumor agents, the first generation of dual indoleamine 2,3-dioxygenase 1 (IDO1) and histone deacetylase (HDAC) inhibitors were designed. The highly active dual inhibitor 10 showed excellent and balanced activity against both IDO1 (IC50 = 69.0 nM) and HDAC1 (IC50 = 66.5 nM), whose dual targeting mechanisms were validated in cancer cells. Compound 10 had good pharmacokinetic profiles as an orally active antitumor agent and significantly reduced the l-kynurenine level in plasma. In particular, it showed excellent in vivo antitumor efficacy in the murine LLC tumor model with low toxicity. This proof-of-concept study provided a novel strategy for cancer treatment. Compound 10 represents a promising lead compound for the development of novel antitumor agents and can also be used as a valuable probe to clarify the relationships and mechanisms between cancer immunotherapy and epigenetics.

| S-EPMC5900342 | biostudies-literature

Strategic Incorporation of Polarity in Heme-Displacing Inhibitors of Indoleamine-2,3-dioxygenase-1 (IDO1).

Project description:Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as a target of significant interest to the field of cancer immunotherapy, as the upregulation of IDO1 in certain cancers has been linked to host immune evasion and poor prognosis for patients. In particular, IDO1 inhibition is of interest as a combination therapy with immune checkpoint inhibition. Through an Automated Ligand Identification System (ALIS) screen, a diamide class of compounds was identified as a promising lead for the inhibition of IDO1. While hit 1 possessed attractive cell-based potency, it suffered from a significant right-shift in a whole blood assay, poor solubility, and poor pharmacokinetic properties. Through a physicochemical property-based approach, including a focus on lowering AlogP98 via the strategic introduction of polar substitution, compound 13 was identified bearing a pyridyl oxetane core. Compound 13 demonstrated improved whole blood potency and solubility, and an improved pharmacokinetic profile resulting in a low predicted human dose.

| S-EPMC7153270 | biostudies-literature

Discovery and Characterisation of Dual Inhibitors of Tryptophan 2,3-Dioxygenase (TDO2) and Indoleamine 2,3-Dioxygenase 1 (IDO1) Using Virtual Screening.

Project description:Cancers express tryptophan catabolising enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2) to produce immunosuppressive tryptophan metabolites that undermine patients' immune systems, leading to poor disease outcomes. Both enzymes are validated targets for cancer immunotherapy but there is a paucity of potent TDO2 and dual IDO1/TDO2 inhibitors. To identify novel dual IDO1/TDO2 scaffolds, 3D shape similarity and pharmacophore in silico screening was conducted using TDO2 as a model for both systems. The obtained hits were tested in cancer cell lines expressing mainly IDO1 (SKOV3-ovarian), predominantly TDO2 (A172-brain), and both IDO1 and TDO2 (BT549-breast). Three virtual screening hits were confirmed as inhibitors (TD12, TD18 and TD34). Dose response experiments showed that TD34 is the most potent inhibitor capable of blocking both IDO1 and TDO2 activity, with the IC50 value for BT549 at 3.42 µM. This work identified new scaffolds able to inhibit both IDO1 and TDO2, thus enriching the collection of dual IDO1/TDO2 inhibitors and providing chemical matter for potential development into future anticancer drugs.

| S-EPMC6930675 | biostudies-literature

Updates in the Clinical Development of Epacadostat and Other Indoleamine 2,3-Dioxygenase 1 Inhibitors (IDO1) for Human Cancers.

Project description:Recent application of immunotherapy in clinical oncology revolutionized our management of advanced human cancers. Check point inhibitors targeting CTLA4 and PD-1/PD-L1 axis are immunotherapeutic agents currently available to treat a variety of cancers. However, a novel therapeutic approach is needed to further improve patient outcome with these agents. Indoleamine 2,3-dioxygenase 1 (IDO1) is a rate-limiting enzyme in the metabolism of essential amino acid tryptophan in the peripheral tissue. IDO1 is overexpressed in human cancer cells and suppresses effector T cell function and promotes regulatory T cells (Tregs). Overexpression of IDO1 is associated with poor patient survival in several types of human cancer. These findings indicate that IDO1 is a promising target that can improve the treatment outcome in the field of Immuno-oncology. Several orally available IDO1 inhibitors including Epacadostat have entered human clinical trials over the last few years without a major safety concern. Although there is no objective response in single-agent trials, combination regimens with PD-1 inhibitors appear to exceed the activity of PD-1 inhibitors alone. Recent phase III ECHO 301 trial testing the combination of Epacadostat with Pembrolizumab in melanoma did not show superior outcome compared to Pembrolizumab alone. This lead to halting of other phase III trials using IDO1 inhibitors. In this minireview, we will discuss the recent clinical development of Epacadostat and other IDO1 inhibitors.

| S-EPMC6180183 | biostudies-literature

Synthesis and Molecular Modeling Studies of N'-Hydroxyindazolecarboximidamides as Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.

Project description:Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme that is highly overexpressed in various cancer cells and antigen-presenting cells. It has emerged as an attractive therapeutic target for cancer immunotherapy, which has prompted high interest in the development of small-molecule inhibitors. To discover novel IDO1 inhibitors, we designed and synthesized a series of N'-hydroxyindazolecarboximidamides. Among the compounds synthesized, compound 8a inhibited both tryptophan depletion and kynurenine production through the IDO1 enzyme. Molecular docking studies revealed that 8a binds to IDO1 with the same binding mode as the analog, epacadostat (INCB24360). Here, we report the synthesis and biological evaluation of these hydroxyindazolecarboximidamides and present the molecular docking study of 8a with IDO1.

| S-EPMC6150275 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data