Dual TDO/IDO Inhibitor / Merck (MSD) - LARVOL DELTA

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

The Double-Edged Sword: The Complex Function of Enteric Glial Cells in Neurodegenerative Diseases. (PubMed, J Neurochem) - "To date, the intracellular mechanisms that define the transcriptional profile expressed in EGCs in each situation have not yet been elucidated. This review proposes a discussion on: (1) the complex role of distinct phenotypes of enteric glial cells involved in neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and multiple sclerosis (MS); and (2) innovative strategies such as IDO/TDO inhibitors, Brazil nuts, caffeic acid, polyphenols, among others, that act on EGCs and have the potential to treat neurodegenerative diseases."

Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Huntington's Disease • Movement Disorders • Multiple Sclerosis • Parkinson's Disease

Efficient and regioselective synthesis of ortho-diiodinated homobenzylic alcohol derivatives: in silico evaluation as potential anticancer IDO/TDO inhibitors. (PubMed, Org Biomol Chem) - "Our analysis shows that our designed compounds have unmatched pharmacological potential, far surpassing previously reported compounds. This highlights the innovative nature of these derivatives and sets a new benchmark in IDO and TDO drug discovery, indicating their significant potential as effective anticancer inhibitors."

Journal • Oncology

Cheminformatics analysis of indoleamine and tryptophan 2,3-dioxygenase inhibitors: A descriptor and fingerprint based machine learning approach to disclose selectivity measures. (PubMed, Comput Biol Med) - "After disappointing results of the epacadostat as a selective IDO inhibitor in phase III clinical trials, there is much interest in the development of the TDO selective inhibitors. In addition, furo[2,3-c]pyridine-2,3-diamine was found as a common fragment for inhibition of the both targets and can be used in the design of the dual target inhibitors of the IDO and TDO. The new fragments introduced here can be a useful building blocks for incorporation into the selective TDO or dual IDO/TDO inhibitors."

Journal • Machine learning • Oncology • Pain • TDO2

A theoretical study on the activity and selectivity of IDO/TDO inhibitors. (PubMed, Phys Chem Chem Phys) - "Furthermore, the binding and dissociation processes of the C1 inhibitor (NLG919) were simulated by the adaptive steering molecular dynamics (ASMD) method, which not only addressed the possible stable, metastable, and transition states for C1 inhibitor-IDO/TDO interactions, but also accurately predicted kinetic data for C1 inhibitor binding and dissociation. In conclusion, we have constructed a complete process from enzyme (IDO/TDO) conformational activation to inhibitor binding/dissociation and used the thermodynamic and kinetic data of each link as clues to verify the control mechanism of IDO/TDO on inhibitor selectivity. This is of great significance for us to understand the design principles of tumor immunotherapy drugs and to avoid drug resistance of immunotherapy drugs."

Journal • Oncology • IDO1

Suppression of Kynurenine 3-Monooxygenase as a Treatment for Triple-negative Breast Carcinoma. (PubMed, Anticancer Res) - "However, studies using IDO/TDO inhibitors against cancer have not yet shown that this type of treatment can be successful...This strategy may be beneficial in the treatment of aggressive breast cancer, particularly in patients with triple-negative breast cancer. A major challenge to this strategy, when searching for an effective treatment for tumors, especially tumors like breast carcinoma that often metastasize to the brain, is finding KMO inhibitors that adequately cross the blood-brain barrier."

Journal • Review • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • IDO1 • TDO2

[VIRTUAL] Metabolomic adaptations and correlates of survival to immune checkpoint blockade (AACR-II 2020) - "To investigate the generalizability of our results, we also performed metabolomics and serum specimens from a large randomized Phase 3 trial (CheckMate 025) with 743 RCC patients, among which 394 received nivolumab and 349 received everolimus. We identified increased tryptophan to kynurenine conversion in response to PD1 blockade in a subset of melanoma and RCC patients. By using independent cohorts, we showed that Kyn/Trp temporal alterations robustly correlated with overall survival of patients receiving nivolumab. Our findings illustrate that checkpoint blockade in combination with IDO/TDO inhibitors might only benefit a selected group of patients with checkpoint-inhibition-triggered kynurenine pathway activation."

Checkpoint inhibition • IO biomarker • Genito-urinary Cancer • Melanoma • Oncology • Renal Cell Carcinoma • Solid Tumor • IDO1 • PD-L1 • TMB

Targeting kynurenine pathway using novel IDO/TDO dual inhibitor (AT0174) to modulate tumor microenvironment in platinum resistant non-small cell lung cancer cancer: An immunometabolism compliment markers (AACR 2022) - "Next, we used a syngeneic mouse model of LLC (Lewis lung cancer) vs cisplatin resistant LLC-CR, to examine the effects of AT-0174 (170 mg/kg; P.O. once daily) in combination with anti-PD1 antibody (10 mg/ml; I.P. once every 3 days)...Treatment with AT-0174 resulted in higher tumor infiltrating lymphocytes of Teffs and NK and lower Treg frequency in LLC-CR tumors than treatment with a selective IDO1 inhibitor (epacadostat)...Support by the Dept. of Veterans Affairs."

Biomarker • IO biomarker • Tumor microenvironment • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD14 • CD4 • CD8 • FOXP3 • IL2RA • NCR1 • NKG2D • PD-L1 • TDO2

[VIRTUAL] Metabolomic adaptations and correlates of survival to immune checkpoint blockade (AACR 2020) - "To investigate the generalizability of our results, we also performed metabolomics and serum specimens from a large randomized Phase 3 trial (CheckMate 025) with 743 RCC patients, among which 394 received nivolumab and 349 received everolimus. We identified increased tryptophan to kynurenine conversion in response to PD1 blockade in a subset of melanoma and RCC patients. By using independent cohorts, we showed that Kyn/Trp temporal alterations robustly correlated with overall survival of patients receiving nivolumab. Our findings illustrate that checkpoint blockade in combination with IDO/TDO inhibitors might only benefit a selected group of patients with checkpoint-inhibition-triggered kynurenine pathway activation."

Checkpoint inhibition • IO Biomarker • Genito-urinary Cancer • Melanoma • Oncology • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer • IDO1 • PD-L1 • TMB

Metabolomic adaptations and correlates of survival to immune checkpoint blockade. (PubMed, Nat Commun) - "Here, in order to investigate the metabolic alterations in response to immune checkpoint blockade, we comprehensively profile serum metabolites in advanced melanoma and renal cell carcinoma patients treated with nivolumab, an antibody against programmed cell death protein 1 (PD1). We identify serum kynurenine/tryptophan ratio increases as an adaptive resistance mechanism associated with worse overall survival. This advocates for patient stratification and metabolic monitoring in immunotherapy clinical trials including those combining PD1 blockade with indoleamine 2,3-dioxygenase/tryptophan 2,3-dioxygenase   (IDO/TDO) inhibitors."

Checkpoint inhibition • Journal

Discovery and optimization of imidazoisoindole-based IDO/TDO dual inhibitors (ACS-Sp 2019) - "Next, activity against IDO was gained through further modification of the same element to arrive at potent dual IDO/TDO inhibitors. Finally, through optimization of compound physical properties, potent and orally bio-available dual inhibitors were identified."

IO Biomarker

Discovery and optimization of imidazoisoindole-based IDO/TDO dual inhibitors (ACS-Sp 2019) - "Next, activity against IDO was gained through further modification of the same element to arrive at potent dual IDO/TDO inhibitors. Finally, through optimization of compound physical properties, potent and orally bio-available dual inhibitors were identified."

IO Biomarker