navoximod (NLG919) / Lumos Pharma - LARVOL DELTA

Adverse pro-tumorigenic effects of IDO1 catalytic inhibitors mediated by the non-enzymatic function of IDO1 in tumor cells. (PubMed, Front Immunol) - "By studying the turnover of IDO1 protein in human tumor cells exposed to various IDO1 catalytic inhibitors, such as epacadostat, linrodostat, and navoximod, we show here that these molecules stabilize a non-enzymatic protein conformation of IDO1, independently of their mechanism of inhibition. In the thyroid carcinoma cell line FTC-133, the stabilized and non-enzymatic IDO1 protein promotes the proliferation and migration of the tumor, resulting in an adverse pro-tumorigenic effect. These results uncover an unexpected adverse effect of IDO1 inhibitors in the tumor microenvironment that overcomes the enzymatic inhibition of IDO1, and suggest protein degradation, rather than enzymatic inhibition, as a more effective approach to target IDO1 in the tumor microenvironment."

Journal • Oncology • Solid Tumor • Targeted Protein Degradation • Thyroid Gland Carcinoma • IDO1

A Tailor-Made Biaryl-Stapled Peptide Nanoprodrug with Esterase-Triggered Dual Immunomodulation for Amplified Cancer Therapy. (PubMed, Nano Lett) - "This nanoprodrug platform features a biaryl-stapled proapoptotic peptide motif covalently conjugated to the indoleamine 2,3-dioxygenase (IDO) inhibitor NLG919 via an ester bond, enabling esterase-triggered payload release within the tumors...In vivo studies demonstrate that this dual-immunomodulatory strategy significantly improves the efficacy of immunotherapy when combined with PD-L1 blockade. This work paves the way to advance the development of stapled peptide-based nanoplatforms as next-generation cancer immunotherapies."

Journal • Immunology • Oncology

IDO and TDO inhibitors in cancer immunotherapy: mechanisms, clinical development, and future directions. (PubMed, Front Pharmacol) - P1 | "Among these, medications like Indoximod, Epacadostat, and Navoximod have shown promise in influencing the immune system and slowing tumor progression, while dual inhibitors like HTI-1090 try to address broader metabolic connections. The use of IDO/TDO inhibitors with conventional anticancer medications demonstrates their potential to reshape cancer treatment paradigms, contingent on further research to optimize efficacy and safety. Clinical Trial Registration: https://clinicaltrials.gov/study/NCT03844438."

Journal • Review • Oncology • TDO2

Ligand-induced conformations and dynamic allosteric motions of IDO1 affecting the recruitment of a protein signaling partner. (PubMed, Commun Chem) - "A few IDO1 inhibitors have reached the clinical stage, including navoximod, epacadostat and linrodostat. Using second harmonic generation analysis (SHG) and molecular dynamics simulations, here we show that these clinical inhibitors can induce distinct allosteric motions in the enzyme that affect the stability of the transient signaling complex between IDO1 and Src tyrosine kinase. Next generation sequencing demonstrates that, despite sharing a similar ability to inhibit the enzyme's catalytic function, all three catalytic inhibitors modulate the IDO1's signaling function in different ways, regulating distinct transcriptomes in SKOV3 cells."

IO biomarker • Journal • Oncology • IDO1

Iridium(III)/rhenium(I) complexes bearing NLG919 as the ligand for enhanced triple-negative breast cancer therapy. (PubMed, Dalton Trans) - "The wound healing and colony assays also prove that these complexes significantly inhibit the metastasis of 4T1 cells. Furthermore, while inducing apoptosis, these complexes can also promote the release of damage-related molecular patterns (calreticulin (CRT), high mobility group protein b1 (HMGB1) and adenosine triphosphate (ATP)), thereby inducing immunogenic cell death (ICD)."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BCL2 • CALR • CASP3 • HMGB1

Iodine-starch chromogenic nanoplatforms for photothermal precision and IDO-mediated colorectal cancer therapy. (PubMed, Int J Biol Macromol) - "They also encapsulated the IDO1 inhibitor NLG919 (IN@ASt NPs), enhancing immune modulation by downregulating IDO1 expression and reducing PTT-induced immunosuppression. This synergy induced immunogenic cell death, activated strong antitumor immunity, and inhibited lung metastasis in CRC models. Thus, this innovative platform leverages the biocompatibility of carbohydrate-based materials to address key challenges in CRC therapy."

IO biomarker • Journal • Colorectal Cancer • Immune Modulation • Immunology • Oncology • Solid Tumor

Expression of indoleamine-2,3-dioxygenase 1 in sebaceous glands and related tumors of the eyelid: a potential diagnostic target. (PubMed, Orbit) - "Prior to these findings, clinical management centered around surgical excision. The use of molecular compounds such as indoximob, epacadostat, BMS-986205 and navoximod, that directly target IDO1 opens new possibilities for targeting these tumors, improving clinical outcomes, and minimizing the morbidities often associated with surgery."

IO biomarker • Journal • Eye Cancer • Oncology • IDO1

Ultrasonic Cavitation-Manipulated Macrophages Hitchhiking Augments Delivery of Nanocarriers for Active and Efficient Cancer Therapy. (PubMed, Adv Healthc Mater) - "The OGNLN is perfluoropentane-loaded liposomal nanodroplet which consists of lipophilic prodrugs of elaidate-conjugated gemcitabine and NLG919...The nanodrugs penetrate tumor parenchyma and exhibit potent antitumor activity via chemo-immunotherapy. This study presents a promising strategy for efficient cancer therapy by utilizing ultrasound-regulated nanodrug-hitchhiking macrophages."

Journal • Oncology • Solid Tumor

Extracellular matrix-degradable polymer nanostimulants elicit potent immune responses in orthotopic pancreatic cancer via sono-activatable dual-drug synergism. (PubMed, Mater Today Bio) - "The SPNs were constructed by loading two immune drugs: toll-like receptor 7/8 agonist (R848) and indoleamine 2,3-dioxygenase inhibitor (NLG919), onto singlet oxygen (1O2)-responsive SPNs, and modifying their surface with hyaluronidase (HAase)...Consequently, the growth of orthotopic pancreatic tumors in mouse models is nearly inhibited, and tumor metastases are effectively suppressed. This study presents an ECM-degradable semiconducting polymer nanostimulant for multifaceted remodeling of the tumor microenvironment, enabling effective and precise immunotherapy of deep-seated orthotopic tumors."

Journal • Oncology • Pancreatic Cancer • Solid Tumor

Engineered Macrophages for Ultrasound-Triggered Drug Release and Enhanced Cancer Therapy (CIMT 2025) - "Esterified prodrugs of gemcitabine and NLG919 were encapsulated into lipid droplets containing perfluoropentane to construct liposome (OGNLN)...In vivo study demonstrated that OGNLN@MACs suppressed tumor growth and prolonged the survival of tumor-bearing mice.In summary, this study developed drug-loaded macrophages (OGNLN@MACs) that enables ultrasound-controlled drug release. This strategy enhances drug delivery efficiency and inhibits tumor progression in a mouse model."

Oncology

Reversing the immunosuppressive tumor microenvironment via "Kynurenine starvation therapy" for postsurgical triple-negative breast cancer treatment. (PubMed, J Control Release) - "Moreover, a single implantation of NLG919 + KYNase@Gel not only effectively inhibits the postoperative recurrence and metastasis in 4 T1 tumor-bearing mice, but also restrains the growth in an orthotopic TNBC mouse model. These findings highlight an innovative strategy to reinforce the antitumor immune response for the treatment of postsurgical TNBC."

Biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • KYNU

Targeting matrix metalloproteinases activating and Indoleamine 2,3-dioxygenase suppression for triple-negative breast Cancer multimodal therapy. (PubMed, Int J Biol Macromol) - "Through self-assembly technology, this micelle effectively incorporates chemotherapy drugs (camptothecin (CPT) and cinnamaldehyde (CA)), reactive oxygen species (ROS) stimulants, nitric oxide (NO) donor and IDO inhibitor (NLG919), where CPT and CA have been reported to help generating ROS mainly in the mitochondrion...Experimental results demonstrate that the micelles exhibit significant anti-tumor effects both in vitro and in vivo, accompanied by favorable biocompatibility. This study provides new insights into the application of subcellular targeting drug delivery systems in TNBC treatment, potentially heralding a new breakthrough in TNBC therapy."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Drug repurposing through Biophysical Insights: Focus on Indoleamine 2,3-Dioxygenase and Tryptophan 2,3-Dioxygenase Dual Inhibitors. (PubMed, Cell Biochem Biophys) - "Despite attempts to use navoximod as a dual-specific inhibitor, its poor bioavailability and lack of clinical efficacy have hampered its utility...Alongside, the interaction profile with critical residues, strongly reinforced DB06292 (Dapagliflozin) as a compelling hit candidate. Finally, the reliability of the result was corroborated through a rigorous 200 ns molecular dynamics simulation, ensuring the stable binding of the hit against the target proteins. Considering the promising outcomes, we speculate that the proposed hit compound holds strong potential for the management of TNBC."

Journal • Oncology • Triple Negative Breast Cancer • IDO1 • TDO2

A novel NIR-dependent IDO-inhibiting ethosomes treatment melanoma through PTT/PDT/immunotherapy synergy. (PubMed, Colloids Surf B Biointerfaces) - "In this study, we prepared and characterized INEs, a novel ethosome composed of the photosensitizer IR251 and the Indoleamine-2, 3-dioxygenase (IDO) inhibitor NLG919...In conclusion, INEs represent a promising strategy for melanoma treatment by a combination of phototherapy and immunotherapy with high safety. This study provides new insights and a theoretical basis for the clinical treatment of melanoma."

Journal • Melanoma • Oncology • Solid Tumor • CD4 • CD8

Novel therapeutic targets uncovered by genome-wide integrative analysis in bronchopulmonary dysplasia. (PubMed, J Matern Fetal Neonatal Med) - "The Drug-Gene Interaction Database (DGIdb) predicted three drugs-LM10, navoximod, and ziprasidone-that potentially interact with these key genes. This integrative genome-wide analysis provides valuable insights into the genetic mechanisms underlying BPD. The findings facilitate the identification of novel therapeutic targets and pave the way for personalized treatment strategies for affected neonates."

Journal • Bronchopulmonary Dysplasia • Pulmonary Disease • Respiratory Diseases

Tumor Microenvironment-Responsive Nano-Immunomodulators for Enhancing Chimeric Antigen Receptor-T Cell Therapy in Lung Cancer. (PubMed, ACS Nano) - "The acidic TME induces the disassembly of FMANAC, followed by the drug release, in which C-C chemokine ligand 5 (CCL5) improves the disrupted chemotactic gradient within tumors, increasing CAR-T cell recruitment and infiltration into deep tissue; and NLG919 reverses indoleamine 2,3-dioxygenase (IDO)-mediated immunosuppression in TME to create a favorable environment for CAR-T cells to exert their killing function. In the H460 lung cancer animal model, this nanoregulatory strategy combined with engineered CD276 CAR-T cells, guided by multiplexed near-infrared-II fluorescence imaging for programmed administration, achieved significantly enhanced tumor treatment efficacy."

Biomarker • Journal • Hematological Disorders • Hematological Malignancies • Lung Cancer • Oncology • Solid Tumor • CD276

NIR-II photothermal therapy combined with activatable immunotherapy against the recurrence and metastasis of orthotopic triple-negative breast cancer. (PubMed, Nanoscale) - "At the same time, NLG NPs can be decomposed into the NLG919 monomer in the tumor microenvironment, which can effectively strengthen the immunogenic cell death-induced immune response. NIR-II PTT in synergy with IDO-1 blockade can effectively inhibit tumor growth and prevent tumor recurrence and metastasis. This work thus provides a safe, efficient and feasible method for the treatment of malignant tumors."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • IDO1

Polyphenol-based pH-responsive nanoparticles enhance chemo-immunotherapy in pancreatic cancer. (PubMed, J Control Release) - "Herein, we propose a concise strategy to construct a biocompatible, polyphenol-based, pH-responsive nanoparticle to co-deliver docetaxel (DTX) and NLG919 (an IDO1 inhibitor) to significantly enhance chemo-immunotherapy for PDAC by remodeling the TME. FPND triggered an effective anti-tumor immune response, characterized by increased CD8+ T cells infiltration and decreased Treg recruitment, leading to significant inhibition of subcutaneous tumor growth in KPC mice through a combination of chemotherapy and immunotherapy. Overall, FPND nanoparticles showed excellent anti-tumor efficacy as a PDAC therapeutic strategy with broad potential in precision medicine."

Journal • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD8

An albumin-prodrug injectable formulation for synergistic cancer immunotherapy. (PubMed, J Colloid Interface Sci) - "Meanwhile, NLG919 regulates the recognition and killing of tumor cells by immune cells, effectively blocking the immunosuppression caused by IDO overexpression. This study highlights the potential of a tumor environment-responsive prodrug strategy to enhance the efficacy of immunotherapy, demonstrating the promising clinical translation of the novel MSA-NLG@BSA (PIF) formulation."

IO biomarker • Journal • Oncology • STING

Redox-responsive metal-organic framework nanocapsules enhance tumor chemo-immunotherapy by modulating tumor metabolic reprogramming. (PubMed, Mater Today Bio) - "DNMCs consist of an acidic and redox-sensitive metal-organic framework (MOF) encapsulating Doxorubicin (DOX) and the indoleamine-2,3-dioxygenase1 (IDO1) inhibitor NLG919. Overall, DNMCs exhibit significant tumor growth inhibition in pancreatic cancer patient-derived organoids (PDOs) and mouse models. This study presents a promising approach to enhancing chemo-immunotherapy by targeting tumor metabolic reprogramming and augmenting immune response against malignant tumors."

Journal • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

Identification of putative Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) dual inhibitors for triple-negative breast cancer therapy. (PubMed, J Biomol Struct Dyn) - "Navoximod, a reliable dual-specific inhibitor, resulted in poor bioavailability and modest efficacy in clinical trials restricts its utility...In light of these findings, it is presumed that the proposed compound exhibits significant inhibitory activity. As a result, we speculate that further optimisation of NPACT00380 could be beneficial for the treatment and management of TNBC."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • IDO1 • TDO2

Injectable supramolecular hydrogel co-loading abemaciclib/NLG919 for neoadjuvant immunotherapy of triple-negative breast cancer. (PubMed, Nat Commun) - "The neoadjuvant immunotherapy reduces tumor recurrence and pulmonary metastasis and prolongs the survival of animals. This hydrogel provides a potential platform for neoadjuvant immunotherapy of triple-negative breast cancer with reduced toxicity compared with free abemaciclib."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • IDO1 • IL2

Pyruvate Kinase M2-Responsive Release of Paclitaxel and Indoleamine 2,3-Dioxygenase Inhibitor for Immuno-Chemotherapy of Nonsmall Cell Lung Cancer. (PubMed, Adv Sci (Weinh)) - "To address this issue, a smart peptide hydrogelator Nap-Phe-Phe-Phe-Lys-Ser-Thr-Gly-Gly-Lys-Ala-Pro-Arg-OH (Nap-T), which co-assembles with PTX and an IDO inhibitor GDC0919 to form a hydrogel GP@Gel Nap-T, is rationally designed. We find that GP@Gel Nap-T enhances the infiltration of tumor-infiltrating immune cells and reduces the number of immunosuppressive cells in either tumor tissues or tumor-draining lymph nodes, thus enhancing the immuno-chemotherapy of PTX toward NSCLC. With this PKM2-responsive drug release strategy, the smart peptide hydrogel platform might be applied for NSCLC treatment in clinic in near future."

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • PKM

Stimulus Responsive Nanocarrier for Enhanced Antitumor Responses Against Hepatocellular Carcinoma. (PubMed, Int J Nanomedicine) - "We have developed a pH and reactive oxygen species (ROS) dual stimulus-responsive drug delivery system (PN@GPB-PEG NPs) loaded with chemotherapeutic paclitaxel (PTX) and indoleamine 2.3-dioxygenase (IDO) inhibitor NLG919, for HCC chemoimmunotherapy. In a mouse model of HCC, our nanoparticles effectively inhibited the growth of primary and recurrent tumors. These encouraging results highlight the potential of our nanocarrier system as an innovative therapeutic approach to address HCC primary tumor and postsurgical recurrence, providing hope for enhanced patient outcomes."

Journal • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

Biomimic Nanodrugs Overcome Tumor Immunosuppressive Microenvironment to Enhance Cuproptosis/Chemodynamic-Induced Cancer Immunotherapy. (PubMed, Adv Sci (Weinh)) - "Elesclomol (ES) as an efficient Cu ionophore can specifically transport Cu into mitochondria and disrupt intracellular Cu homeostasis...Herein, a biomimic nanodrug (ECNM) is fabricated, of which ES, Cu2+ and NLG919 (an IDO1 inhibitor) are integrated via a self-assembly process and subsequently coated with 4T1 cell membrane...Furthermore, ECNM not only accelerates tumor regression but also gains a strong abscopal effect and displays the potential of tumor vaccination. Overall, ECNM can activate antitumor immunity via cuproptosis and CDT, together with TIM reversing, for cancer treatment."

Journal • Oncology