Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias , Sulfonamidas , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Sulfonamidas/uso terapêutico , Neoplasias/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Piperidinas/uso terapêutico , OximasRESUMO
The over-activation of tryptophan (Trp) metabolism to kynurenine (Kyn) catalyzed by Indoleamine 2,3-dioxygenase-1 (IDO1) enzyme, is one of the main metabolic pathways involved in tumor microenvironment (TME) immune escape and cancer treatment failure. The most efficient of IDO1 inhibitors is Epacadostat (EPA). Since monotherapy with single-agent IDO1 inhibitor regimen has led to an insufficient anti-tumor activity, we examined the efficacy of simultaneous treatment by Liposomal epacadostat (Lip-EPA) as a potent IDO inhibitor, in combination with docetaxel (DTX) as a complement immunogenic cell death (ICD) agent against B16F10 model. First, the in vitro combination index (CI) of epacadostat (EPA) and DTX was investigated by using the unified theory. Then, the in vivo efficacy of the combination therapy was assessed. Results indicated the synergestic cytotoxic effect of the combination on B16F10 compared to normal fibroblast cells (NIH). The immune profiling demonstrated a significant increase in the percentage of infiltrated T lymphocytes and IFN-γ release, a significant decrease in the percentage of regulatory T cells (Treg) population and the subsequent low levels of IL-10 generation in mice treated with Lip-EPA + DTX. Further, a significant tumor growth delay (TGD = 69.15 %) and an increased life span (ILS > 47.83 %) was observed with the combination strategy. Histopathology analysis revealed a remarkable increase in the Trp concentration following combination treatment, while Kyn levels significantly decreased. Results showed that the nano-liposomal form of IDO1 inhibitor in combination with chemotherapy could significantly improve the imunity response and dominate the tumor immuno-suppressive micro-environment, which merits further investigations.
Assuntos
Docetaxel , Indolamina-Pirrol 2,3,-Dioxigenase , Lipossomos , Melanoma Experimental , Camundongos Endogâmicos C57BL , Sulfonamidas , Microambiente Tumoral , Animais , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/imunologia , Sulfonamidas/farmacologia , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Camundongos , Linhagem Celular Tumoral , Imunoterapia/métodos , Oximas/farmacologia , Oximas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Feminino , Nanopartículas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
Introduction: Chemotherapy is still the treatment of choice for advanced triple-negative breast cancer. Chemotherapy combined with immunotherapy is being tried in patients with triple-negative breast cancer. As a kind of "cold tumor", triple-negative breast cancer has a bottleneck in immunotherapy. Indoleamine 2, 3-dioxygenase-1 inhibitors can reverse the immunosuppressive state and enhance the immune response. Methods: In this study, mesoporous silica nanoparticles were coated with the chemotherapeutic drug doxorubicin and indoleamine 2, 3-dioxygenase 1 inhibitor 1-Methyl-DL-tryptophan (1-MT), and then encapsulate the surfaces of a triple-negative breast cancer cell membrane to construct the tumor dual-targeted delivery system CDIMSN for chemotherapy and immunotherapy, and to investigate the immunogenic death effect of CDIMSN. Results and discussion: The CDIMSN could target the tumor microenvironment. Doxorubicin induced tumor immunogenic death, while 1-MT reversed immunosuppression. In vivo findings showed that the tumor size in the CDIMSN group was 2.66-fold and 1.56-fold smaller than that in DOX and DIMSN groups, respectively. CDIMSN group was better than naked DIMSN in stimulating CD8+T cells, CD4+T cells and promoting Dendritic Cells(DC) maturation. In addition, blood analysis, biochemical analysis and Hematoxylin staining analysis of mice showed that the bionic nanoparticles had good biological safety.
Assuntos
Dioxigenases , Inibidores Enzimáticos , Neoplasias de Mama Triplo Negativas , Animais , Humanos , Camundongos , Biomimética , Dioxigenases/antagonistas & inibidores , Doxorrubicina/farmacologia , Imunoterapia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Microambiente TumoralRESUMO
Indoleamine-2,3-dioxygenase 1 (IDO1) is an immunomodulatory enzyme known to catalyse the initial and rate limiting step of kynurenine pathway of l-tryptophan metabolism. IDO1 enzyme over expression plays a crucial role in progression of cancer, malaria, multiple sclerosis and other life-threatening diseases. Several efforts over the last two decades have been invested by the researchers for the discovery of different IDO1 inhibitors and the plasticity of the IDO1 enzyme ligand binding pocket provide ample opportunities to develop new heterocyclic scaffolds targeting this enzyme. In the present work, based on the X-ray crystal structure of human IDO1 coordinated with few ligands, we designed and synthesized new fused heterocyclic compounds and evaluated their potential human IDO1 inhibitory activity (compound 30 and 41 showed IC50 values of 23 and 13 µM, respectively). The identified HITs were observed to be non-toxic to HEK293 cells at 100 µM concentration. The observed activity of the synthesized compounds was correlated with the specific interactions of their structures at the enzyme pocket using docking studies. A detailed analysis of docking results of the synthesized analogues as well as selected known IDO1 inhibitors revealed that most of the inhibitors have some reasonable docking scores in at least two crystal structures and have similar orientation as that of co-crystal ligands.
Assuntos
Inibidores Enzimáticos , Indolamina-Pirrol 2,3,-Dioxigenase , Humanos , Relação Estrutura-Atividade , Inibidores Enzimáticos/química , Células HEK293 , Ligação ProteicaRESUMO
Cancer is one of the severe diseases in which abnormal cells divide and proliferate in an uncontrolled manner without any regulation. Globally cancer is among the leading causes of death; according to a recent report of by the WHO, around 10 million people died in 2018 due to cancer. It has also been reported that by 2040, approximately 30 million new cases will be reported every year. The increase in the incidences of cancer is taking a toll on the health care system worldwide. Considerable scientific literature is available on anticancer agents but newer therapeutic strategies are still required in this field to address novel approaches to drug design and discovery to counter this problem. Imidazothiazole represents a privileged scaffold in medicinal chemistry and provides the medicinal chemist the possibility to modulate the physiochemical properties of the lead compound. In recent times, imidazothiazole scaffold is broadly explored for its anticancer activity, which acts through various mechanisms such as EGFR, B-RAF, DHFR kinase inhibition and tubulin polymerization inhibition and other molecular mechanisms of action. Due to their feasible synthetic accessibility and promising pharmacological profile, it has attracted various medicinal chemists to explore and develop imidazothiazole derivatives as potent and safe anticancer agents. In the present article, we have reviewed various potent imidazothiazole scaffold-based derivatives reported as anticancer agents, their synthetic strategies, Structure Activity Relationship (SAR), mechanism of action, and molecular docking along with their future perspective. This review will be very useful for medicinal chemists for drug design and development of imidazothiazole-based potent antiproliferative agents.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Neoplasias/tratamento farmacológico , Desenho de Fármacos , Estrutura MolecularRESUMO
Indoleamine 2,3-dioxygenase-1 (IDO1) has been considered as an attractive target for oncology immunotherapy due to its immunosuppressive effects on the tumor microenvironment. The most advanced IDO1 inhibitor epacadostat in combination with anti-PD-1 antibody failed to show desirable objective response. Epacadostat is now reevaluated in phase III clinical trials, but its pharmacokinetic (PK) properties are unsatisfactory. To further unravel the antitumor efficacy of IDO1 inhibitors, we designed a series of epacadostat analogues by introducing various urea-containing side chains. In particular, the most active compound 3 showed superior inhibitory potency against recombinant hIDO1 and hIDO1 in HeLa cells induced by interferon γ (IFNγ) relative to epacadostat (3, biochemical hIDO1 IC50 = 67.4 nM, HeLa hIDO1 IC50 = 17.6 nM; epacadostat, biochemical hIDO1 IC50 = 75.9 nM, HeLa hIDO1 IC50 = 20.6 nM). Moreover, compound 3 exhibited improved physicochemical properties and rat PK profile with better oral exposure and bioavailability compared with epacadostat. Importantly, this compound exhibited comparable antitumor efficacy with epacadostat in LLC syngeneic xenograft models. Hence, compound 3 represents a promising lead compound for discovery of more effective IDO1 inhibitors.
Assuntos
Inibidores Enzimáticos , Indolamina-Pirrol 2,3,-Dioxigenase , Humanos , Ratos , Animais , Inibidores Enzimáticos/química , Células HeLa , Ureia/farmacologia , Oxidiazóis/químicaRESUMO
Colorectal cancer (CRC) is the third most common cancer in the world. Recently, many clinical studies have demonstrated the therapeutic potential of immune checkpoint therapy combined with inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2) in colon cancer. Compound B37, identified in our previous experiment, is an apo-form indoleamine-2,3-dioxygenase 1 inhibitor (apo-IDO1 inhibitor), which has been shown to significantly suppress tumor growth combined with an anti-PD1 antibody. We speculated whether this apo-IDO inhibitor (B37) combined with a VEGFR2 inhibitor (apatinib) would further improve its anti-tumor activity. Therefore, a syngeneic mouse colon cancer model (mouse colon cancer cell line CT26) was established to investigate the anti-tumor activity of B37 combined with apatinib. As expected, the combination of B37 and apatinib (VEGFR2 inhibitor) improved the therapeutic effect compared with apo-IDO1 inhibitor and apatinib monotherapy, as shown by the reduced growth of transplanted tumors, weakened proliferation, and increased apoptosis of cancer cells. Specifically, there was a 24.8% reduction in tumor volume using apatinib and 31.3% reduction using B37. The combination-treated group showed remarkable inhibition of tumor growth (52.2%). For tumor weight, there was a 29.2% reduction in the apatinib-treated group and 35.0% reduction in the B37-treated group. The combination-treated group showed a 56.3% reduction. Moreover, the combination therapy reprogrammed the immune microenvironment by increasing infiltration of CD4+ and CD8+ T cells, decreasing the ratio of regulatory T cells, and promoting the killing ability of T cells manifested by elevated expression of IFN-γ and granzyme B in the combination-treated group. Our study indicates that the combination of apo-IDO1 inhibitor and apatinib is a promising strategy for CRC therapy.
Assuntos
Neoplasias do Colo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Camundongos , Animais , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Granzimas , Linfócitos T CD8-Positivos/metabolismo , Fator A de Crescimento do Endotélio Vascular , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the rate-limiting step in tryptophan catabolism along the kynurenine (Kyn) pathway and exerts immunosuppressive properties mainly via activation of transcription factor aryl hydrocarbon receptor (AhR) pathway. IDO1 induces NK cells dysfunction via downregulation of the activating receptor NKG2D on NK cells, but whether and how it affects the expression of NKG2D Ligand (NKG2DL) on tumor cells remains unclear. Since a disintegrin and metalloprotease 10 (ADAM10) plays a potential role in the shedding of NKG2DL and the releasing of soluble NKG2DL (sNKG2DL), we investigated how IDO1 modulates the expression of NKG2DL via ADAM10 in non-small cell lung cancer (NSCLC). We found that IDO1 expression was negatively correlated with NKG2DL expression while positively correlated with ADAM10 expression with human lung cancer brain metastasis tissue, NSCLC cells and LLC tumor-bearing mice. IDO1 could regulate ADAM10 expression via IDO1-Kyn-AhR signaling pathway and subsequently regulate NKG2DL expression. IDO1 deficiency led to retarded tumor growth and improved NK cells function in NSCLC mice. IDO1 inhibitors improved NK cells function in vitro and in vivo. The combo of IDO1 inhibitor and NK cells exhibited more therapeutic efficacy than either of the single IDO1 inhibitor or NK cells treatment.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Neoplasias Pulmonares , Proteína ADAM10/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Regulação para Baixo , Humanos , Células Matadoras Naturais/metabolismo , Cinurenina/metabolismo , Ligantes , Neoplasias Pulmonares/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismoRESUMO
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.
Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Estrutura Molecular , Neoplasias , Proteólise/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/químicaRESUMO
Osteoarthritis (OA) is a serious joint inflammation that leads to cartilage degeneration and joint dysfunction. Mesenchymal stem cells (MSCs) are used as a cell-based therapy that showed promising results in promoting cartilage repair. However, recent studies and clinical trials explored unsatisfied outcomes because of slow chondrogenic differentiation and increased calcification without clear reasons. Here, we report that the overexpression of indoleamine 2,3 dioxygenase 1 (IDO1) in the synovial fluid of OA patients impairs chondrogenic differentiation of MSCs in the joint of the OA mice model. The effect of MSCs mixed with IDO1 inhibitor on the cartilage regeneration was tested compared to MSCs mixed with IDO1 in the OA animal model. Further, the mechanism exploring the effect of IDO1 on chondrogenic differentiation was investigated. Subsequently, miRNA transcriptome sequencing was performed for MSCs cocultured with IDO1, and then TargetScan was used to verify the target of miR-122-5p in the SF-MSCs. Interestingly, we found that MSCs mixed with IDO1 inhibitor showed a significant performance to promote cartilage regeneration in the OA animal model, while MSCs mixed with IDO1 failed to stimulate cartilage regeneration. Importantly, the overexpression of IDO1 showed significant inhibition to Sox9 and Collagen type II (COL2A1) through activating the expression of ß-catenin, since inhibiting of IDO1 significantly promoted chondrogenic signaling of MSCs (Sox9, COL2A1, Aggrecan). Further, miRNA transcriptome sequencing of SF-MSCs that treated with IDO1 showed significant downregulation of miR-122-5p which perfectly targets Wnt1. The expression of Wnt1 was noticed high when IDO1 was overexpressed. In summary, our results suggest that IDO1 overexpression in the synovial fluid of OA patients impairs chondrogenic differentiation of MSCs and cartilage regeneration through downregulation of miR-122-5p that activates the Wnt1/ß-catenin pathway.
Assuntos
Condrogênese/fisiologia , Indolamina-Pirrol 2,3,-Dioxigenase/farmacologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Osteoartrite do Joelho/patologia , Animais , Artrite Experimental/enzimologia , Artrite Experimental/patologia , Cartilagem Articular/fisiologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Condrogênese/efeitos dos fármacos , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Osteoartrite do Joelho/enzimologia , Ratos , Ratos Wistar , Regeneração/efeitos dos fármacos , Regeneração/fisiologia , Líquido Sinovial/enzimologiaRESUMO
Immune checkpoint blockade leads to unprecedented responses in many cancer types. An alternative method of unleashing anti-tumor immune response is to target immunosuppressive metabolic pathways like the indoleamine 2,3-dioxygenase (IDO) pathway. Despite promising results in Phase I/II clinical trials, an IDO-1 inhibitor did not show clinical benefit in a Phase III clinical trial. Since, a treatment can be quite effective in a specific subset without being effective in the whole cancer type, it is important to identify the subsets of cancers that may benefit from IDO-1 inhibitors. In this study, we looked for the genomic and immunologic correlates of IDO pathway expression in cancer using the Cancer Genome Atlas (TCGA) dataset. Strong CD8+ T-cell infiltration, high mutation burden, and expression of exogenous viruses [Epstein-Barr virus (EBV), Human papilloma virus (HPV), and Hepatitis C virus (HCV)] or endogenous retrovirus (ERV3-2) were associated with over-expression of IDO-1 in most cancer types, IDO-2 in many cancer types, and TDO-2 in a few cancer types. High mutation burden in ER+ HER2- breast cancer, and ERV3-2 expression in ER- HER2- and HER2+ breast, colon, and endometrial cancers were associated with over-expression of all three genes. These results may have important implications for guiding development clinical trials of IDO-1 inhibitors.
RESUMO
A novel series of IDO1 inhibitors have been identified with good IDO1 Hela cell and human whole blood activity. These inhibitors contain an indoline or a 3-azaindoline scaffold. Their structure-activity-relationship studies have been explored. Compounds 37 and 41 stood out as leads due to their good potency in IDO1 Hela assay, good IDO1 unbound hWB IC50s, reasonable unbound clearance, and good MRT in rat and dog PK studies.
Assuntos
Compostos Aza/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indóis/farmacologia , Animais , Compostos Aza/síntese química , Compostos Aza/química , Cães , Relação Dose-Resposta a Droga , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Indóis/síntese química , Indóis/química , Masculino , Estrutura Molecular , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the first and rate-limiting step in catabolism of tryptophan via the kynurenine pathway, which plays a pivotal role in the proliferation and differentiation of T cells. IDO1 has been proven to be an attractive target for many diseases, such as breast cancer, lung cancer, colon cancer, prostate cancer, etc. In this study, docking-based virtual screening and bioassays were conducted to identify novel inhibitors of IDO1. The cellular assay demonstrated that 24 compounds exhibited potent inhibitory activity against IDO1 at micromolar level, including 8 compounds with IC50 values below 10 µM and the most potent one (compound 1) with IC50 of 1.18 ± 0.04 µM. Further lead optimization based on similarity searching strategy led to the discovery of compound 28 as an excellent inhibitor with IC50 of 0.27 ± 0.02 µM. Then, the structure-activity relationship of compounds 1, 2, 8 and 14 analogues is discussed. The interaction modes of two compounds against IDO1 were further explored through a Python Based Metal Center Parameter Builder (MCPB.py) molecular dynamics simulation, binding free energy calculation and electrostatic potential analysis. The novel IDO1 inhibitors of compound 1 and its analogues could be considered as promising scaffold for further development of IDO1 inhibitors.
Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Desenho de Fármacos , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/química , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-AtividadeRESUMO
Indoleamine-2,3-dioxygenase 1 (IDO1) catalyses the first and rate limiting step of kynurenine pathway accounting for the major contributor of L-Tryptophan degradation. The Kynurenine metabolites are identified as essential cofactors, antagonists, neurotoxins, immunomodulators, antioxidants as well as carcinogens. The catalytic active site of IDO1 enzyme consists of hydrophobic Pocket-A positioned in the distal heme site and remains connected to a second hydrophobic Pocket-B towards the entrance of the active site. IDO1 enzyme also relates directly to the modulation of the innate and adaptive immune system. Various studies proved that the over expression of IDO1 enzyme play a predominant role in the escape of immunity during cancer progression. Recently, there has been considerable interest in evaluating the potential of IDO1 inhibitors to mobilize the body's immune system against solid tumours. In the last two decades, enormous attempts to advance new IDO1 inhibitors are on-going both in pharmaceutical industries and in academia which resulted in the discovery of a diverse range of selective and potent IDO1 inhibitors. The IDO1 inhibitors have therapeutic utility in various diseases and in the near future, it may have utility in the treatment of COVID-19. Despite various reviews on IDO1 inhibitors in last five years, none of the reviews provide a complete overview of diverse chemical space including naturally occurring and synthetic IDO1 inhibitors with detailed structure activity relationship studies. The present work provides a complete overview on the IDO1 inhibitors known in the literature so far along with the Structure-Activity Relationship (SAR) in each class of compounds.
Assuntos
Tratamento Farmacológico da COVID-19 , Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Produtos Biológicos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Humanos , Relação Estrutura-AtividadeRESUMO
INTRODUCTION: Indoleamine 2,3-dioxygenase 1 (IDO1) has been considered as an attractive intracellular target for the development of small-molecule cancer immunotherapy. Results in human clinical studies indicated that the first-generation IDO1 inhibitor epacadostat lacked anticancer activity when combined with the anti-PD-1 antibody pembrolizumab. Epacadostat inhibits IDO1 activity by forming a tertiary IDO1-heme-inhibitor complex. Recently, IDO1 inhibitors capable of displacing the heme group to form a binary high-affinity complex have been discovered and investigated in humans. AREAS COVERED: Structures, mode of action, preclinical activities, and status of clinical development are discussed and compared between the two classes of IDO1 inhibitors that bind to IDO1 protein in the presence (holo-IDO1) or absence (apo-IDO1) of the heme group, respectively. By selectively displacing the heme from IDO1 enzymes, apo-IDO1 inhibitors demonstrate high target selectivity, durable target engagement, and exceptional potency in cellular assays. Data from publications, patent disclosures, and conference proceedings as recent as 2019 are analyzed and summarized. EXPERT OPINION: The outcomes in cancer patients for the first-generation IDO1 inhibitors were disappointing. However, the unique mode of action by the heme-displacing IDO1 inhibitors might help their successful clinical translation and provide a novel class of anticancer drugs for cancer immunotherapy.
Assuntos
Antineoplásicos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Animais , Desenvolvimento de Medicamentos , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Heme/metabolismo , Humanos , Imunoterapia/métodos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Neoplasias/enzimologia , Neoplasias/imunologiaRESUMO
Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are promising drug development targets due to their implications in pathologies such as cancer and neurodegenerative diseases. The search for IDO1 inhibitor has been intensely pursued but there is a paucity of potent TDO and IDO1/TDO dual inhibitors. Natural product tryptanthrin has been confirmed to bear IDO1 and/or TDO inhibitory activities. Herein, twelve novel tryptanthrin derivatives were synthesized and evaluated for the IDO1 and TDO inhibitory potency. All of the compounds were found to be IDO1/TDO dual inhibitors, in particular, compound 9a and 9b bore IDO1 inhibitory activity similar to that of INCB024360, and compound 5a and 9b had remarkable TDO inhibitory activity superior to that of the well-known TDO inhibitor LM10. This work enriches the collection of IDO1/TDO dual inhibitors and provides chemical molecules for potential development into drugs.
Assuntos
Inibidores Enzimáticos/síntese química , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Quinazolinas/química , Triptofano Oxigenase/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/metabolismo , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Concentração Inibidora 50 , Quinazolinas/metabolismo , Solubilidade , Relação Estrutura-Atividade , Triptofano Oxigenase/metabolismoRESUMO
Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing intracellular enzyme that catalyzes the first and rate-determining step of tryptophan metabolism and is an important immunotherapeutic target for the treatment of cancer. In this study, we designed and synthesized a new series of compounds as potential IDO1 inhibitors. These compounds were then evaluated for inhibitory activity against IDO1 and tryptophan 2,3-dioxygenase (TDO). Among them, the three phenyl urea derivatives i12, i23, i24 as showed potent IDO1 inhibition, with IC50 values of 0.1-0.6 µM and no compound exhibited TDO inhibitory activity. Using molecular docking, we predicted the binding mode of compound i12 within IDO1. Compound i12 was further investigated by determining its in vivo pharmacokinetic profile and anti-tumor efficacy. The pharmacokinetic study revealed that compound i12 had satisfactory properties in mice, with moderate plasma clearance (22.45 mL/min/kg), acceptable half-life (11.2 h) and high oral bioavailability (87.4%). Compound i12 orally administered at 15 mg/kg daily showed tumor growth inhibition (TGI) of 40.5% in a B16F10 subcutaneous xenograft model and 30 mg/kg daily showed TGI of 34.3% in a PAN02 subcutaneous xenograft model. In addition, the body weight of i12-treated mice showed no obvious reduction compared with the control group. Overall, compound i12 is a potent lead compound for developing IDO1 inhibitors and anti-tumor agents.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos , Indolamina-Pirrol 2,3,-Dioxigenase , Melanoma Experimental , Proteínas de Neoplasias , Compostos de Fenilureia , Animais , Linhagem Celular Tumoral , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/química , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/enzimologia , Melanoma Experimental/patologia , Camundongos , Simulação de Acoplamento Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/farmacologia , Relação Estrutura-AtividadeRESUMO
BACKGROUND AND PURPOSE: Indoleamine 2, 3-dioxygenase 1 (IDO1) has been linked to neuropathic pain and IDO1 inhibitors have been shown to reduce pain in animals. Some studies have indicated that IDO1 expression increased after neuropathic pain in hippocampus and spinal cord, whether these changes existing in anterior cingulate cortex (ACC) and amygdala remains obscure and how IDO1 inhibition leads to analgesia is largely unknown. Here, we evaluated the antinociceptive effect of PCC0208009, an indirect IDO1 inhibitor, on neuropathic pain and examined the related neurobiological mechanisms. EXPERIMENTAL APPROACH: The effects of PCC0208009 on pain, cognition and anxiogenic behaviors were evaluated in a rat model of neuropathic pain. Motor disorder, sedation and somnolence were also assessed. Biochemical techniques were used to measure IDO1-mediated signaling changes in ACC and amygdala. KEY RESULTS: In rats receiving spinal nerve ligation (SNL), IDO1 expression level was increased in ACC and amygdala. PCC0208009 attenuated pain-related behaviors in the formalin test and SNL model and increased cognition and anxiogenic behaviors in SNL rats at doses that did not affect locomotor activity and sleeping. PCC0208009 inhibited IDO1 expression in ACC and amygdala by inhibiting the IL-6-JAK2/STAT3-IDO1-GCN2-IL-6 pathway. In addition, PCC0208009 reversed synaptic plasticity at the functional and structural levels by suppressing NMDA2B receptor and CDK5/MAP2 or CDK5/Tau pathway in ACC and amygdala. CONCLUSION AND IMPLICATIONS: These results support the role of IDO1-mediated molecular mechanisms in neuropathic pain and suggest that the IDO1 inhibitor PCC0208009 demonstrates selective pain suppression and could be a useful pharmacological therapy for neuropathic pain.
Assuntos
Tonsila do Cerebelo/metabolismo , Analgésicos/uso terapêutico , Giro do Cíngulo/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Neuralgia/tratamento farmacológico , Plasticidade Neuronal/efeitos dos fármacos , Tetrazóis/uso terapêutico , Analgésicos/farmacocinética , Animais , Comportamento Animal/efeitos dos fármacos , Comorbidade , Modelos Animais de Doenças , Formaldeído/farmacologia , Hiperalgesia/tratamento farmacológico , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuralgia/metabolismo , Medição da Dor , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Tetrazóis/farmacocinéticaRESUMO
Indoleamine 2,3-dioxygenase (IDO1) is a key regulator of immune suppression by catalyzing the oxidation of L-tryptophan. IDO1 expression has been related to poor prognosis in several cancers and to resistance to checkpoint immunotherapies. We describe the characterization of a novel small molecule IDO1 inhibitor, NTRC 3883-0, in a panel of biochemical and cell-based assays, and various cancer models. NTRC 3883-0 released the inhibitory effect of IDO1 on CD8-positive T cell proliferation in co-cultures of IDO1-overexpressing cells with healthy donor lymphocytes, demonstrating its immune modulatory activity. In a syngeneic mouse model using IDO1-overexpressing B16F10 melanoma cells, NTRC 3883-0 effectively counteracted the IDO1-induced modulation of L-tryptophan and L-kynurenine levels, demonstrating its in vivo target modulation. Finally, we studied the expression and activity of IDO1 in primary cell cultures established from the malignant ascites of ovarian cancer patients. In these cultures, IDO1 expression was induced upon stimulation with IFNγ, and its activity could be inhibited by NTRC 3883-0. Based on these results, we propose the use of ascites cell-based functional assays for future patient stratification. Our results are discussed in light of the recent discontinuation of clinical trials of more advanced IDO1 inhibitors and the reconsideration of IDO1 as a valid drug target.
Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Melanoma Experimental/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Cinurenina/metabolismo , Melanoma Experimental/metabolismo , Camundongos , Triptofano/metabolismoRESUMO
Indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan catabolising enzyme, is known as a tumour cell survival factor that causes immune escape in several types of cancer. Flavonoids of Sophora flavescens have a variety of biological benefits for humans; however, cancer immunotherapy effect has not been fully investigated. The flavonoids (1-6) isolated from S. flavescens showed IDO1 inhibitory activities (IC50 4.3-31.4 µM). The representative flavonoids (4-6) of S. flavescens were determined to be non-competitive inhibitors of IDO1 by kinetic analyses. Their binding affinity to IDO1 was confirmed using thermal stability and surface plasmon resonance (SPR) assays. The molecular docking analysis and mutagenesis assay revealed the structural details of the interactions between the flavonoids (1-6) and IDO1. These results suggest that the flavonoids (1-6) of S. flavescens, especially kushenol E (6), as IDO1 inhibitors might be useful in the development of immunotherapeutic agents against cancers.