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DRUG:

Dual TDO/IDO Inhibitor

i
Other names: Dual TDO/IDO Inhibitor
Associations
Trials
Company:
Merck (MSD)
Drug class:
IDO inhibitor, Tryptophan 2,3-dioxygenase inhibitor
Associations
Trials
4ms
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
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TDO2 (Tryptophan 2,3-Dioxygenase)
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epacadostat (INCB024360) • Dual TDO/IDO Inhibitor
6ms
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
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IDO1 (Indoleamine 2,3-dioxygenase 1)
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Dual TDO/IDO Inhibitor • navoximod (NLG919)
12ms
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.
Review • Journal
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IDO1 (Indoleamine 2,3-dioxygenase 1) • TDO2 (Tryptophan 2,3-Dioxygenase)
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Dual TDO/IDO Inhibitor
over2years
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.
PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8) • IL2RA (Interleukin 2 receptor, alpha) • CD4 (CD4 Molecule) • CD14 (CD14 Molecule) • FOXP3 (Forkhead Box P3) • TDO2 (Tryptophan 2,3-Dioxygenase) • NCR1 (Natural Cytotoxicity Triggering Receptor 1) • NKG2D (killer cell lectin like receptor K1)
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IDO1 expression
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cisplatin • epacadostat (INCB024360) • Dual TDO/IDO Inhibitor
over4years
[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 • Tumor Mutational Burden • PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • TMB (Tumor Mutational Burden) • IDO1 (Indoleamine 2,3-dioxygenase 1)
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PD-L1 expression
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Opdivo (nivolumab) • everolimus • Dual TDO/IDO Inhibitor • IDO/TDO dual inhibitor
over4years
[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 • Tumor Mutational Burden • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • TMB (Tumor Mutational Burden) • IDO1 (Indoleamine 2,3-dioxygenase 1)
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PD-L1 expression
|
Opdivo (nivolumab) • everolimus • Dual TDO/IDO Inhibitor • IDO/TDO dual inhibitor