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DRUG:

tilarginine (L-NMMA)

i
Other names: L-NMMA, ANO-1020, N-Monomethyl-arginine, NG-monomethyl-l-arginine
Company:
Arginox Pharma, Houston Methodist Research Institute
Drug class:
pan-NOS inhibitor
3ms
Phase Ib of L-NMMA and Pembrolizumab (clinicaltrials.gov)
P1, N=12, Active, not recruiting, The Methodist Hospital Research Institute | Trial completion date: Dec 2023 --> Dec 2024
Trial completion date • Combination therapy • Mismatch repair • Tumor mutational burden • IO biomarker • Metastases
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PD-L1 (Programmed death ligand 1) • BRAF (B-raf proto-oncogene) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability)
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Keytruda (pembrolizumab) • tilarginine (L-NMMA)
8ms
Helicobacter pylori secretary Proteins-Induced oxidative stress and its role in NLRP3 inflammasome activation. (PubMed, Cell Immunol)
Cells were also treated with 10 μM of NOS2 inhibitor l-NMMA and 10 μM of N-acetyl cysteine (NAC), a free radical scavenger·H2O2 (100 μM) treated and untreated cells were used as positive controls and negative control respectively...The low levels of NO and MPO regulates gastrointestinal tract homeostasis and overcomes the inflammatory response of NLRP3. The ROS also plays crucial role in macrophage polarization hence alter the immune responses duing H. pylori pathogenesis.
Journal
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CD163 (CD163 Molecule) • NLRP3 (NLR Family Pyrin Domain Containing 3) • NOS2 (Nitric Oxide Synthase 2) • CD86 (CD86 Molecule) • MPO (Myeloperoxidase)
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tilarginine (L-NMMA)
9ms
Tumor-Associated Monocytes Reprogram CD8+ T Cells into Central Memory-Like Cells with Potent Antitumor Effects. (PubMed, Adv Sci (Weinh))
L-NMMA, a pan nitric oxide synthase inhibitor, can mitigate TAMo-mediated inhibition of T cell proliferation without affecting TCM -like cell generation...Thus, the terminally differentiated TAMo subset (CD300LGhigh ACElow ) mainly contributes to TCM -like cell development. Taken together, these findings establish the significance of TAMos in boosting T-cell antitumor immunity.
Journal
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CD8 (cluster of differentiation 8)
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tilarginine (L-NMMA)
1year
Glioma-derived factors induce an immune suppressive phenotype in bone marrow-derived CCR2+ myeloid cells (SITC 2023)
NOS inhibitor, L-NMMA, was used to evaluate the role of nitric oxide in M-MDSC-mediated T cell suppression...Conclusions Glioma-derived factors recruit and induce CCR2+/CX3CR1+ myeloid cells to a CD4/8+ T cell suppressive state that can be partially ameliorated by iNOS inhibition. While additional M-MDSC-mediated immune suppressive mechanisms need to be identified, targeting M-MDSCs holds promise as an effective approach to improve immune-directed interventions in GBM.
PD(L)-1 Biomarker • IO biomarker
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CD8 (cluster of differentiation 8) • IL6 (Interleukin 6) • CD4 (CD4 Molecule) • CCL2 (Chemokine (C-C motif) ligand 2) • CCR2 (C-C Motif Chemokine Receptor 2) • CX3CR1 (C-X3-C Motif Chemokine Receptor 1)
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tilarginine (L-NMMA)
over1year
Nitric oxide synthase inhibitors as potential therapeutic agents for gliomas: A systematic review. (PubMed, Nitric Oxide)
Glioblastomas remain a challenging therapeutic target. iNOS inhibitors exhibit substantial potential as treatment options for oncologic lesions, and they have demonstrated a safe toxicity profile in humans for other pathological conditions. Research endeavors should be focused on investigating their potential effects on brain tumors.
Review • Journal
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temozolomide • tilarginine (L-NMMA)
over1year
Phase Ib of L-NMMA and Pembrolizumab (clinicaltrials.gov)
P1, N=12, Active, not recruiting, The Methodist Hospital Research Institute | Trial completion date: Jan 2023 --> Dec 2023
Trial completion date • Combination therapy • Mismatch repair • Tumor mutational burden • IO biomarker • Metastases
|
PD-L1 (Programmed death ligand 1) • BRAF (B-raf proto-oncogene) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability)
|
PD-L1 expression • TMB-H • MSI-H/dMMR • BRAF mutation
|
Keytruda (pembrolizumab) • tilarginine (L-NMMA)
over1year
NOS inhibition enhances docetaxel-mediated anti-tumor effect in obese mice with triple negative breast cancer (AACR 2023)
HFD mice had a pro-inflammatory profile with a significantly faster tumor growth and higher expression of iNOS in tumor and adipose tissues. Treatment with the docetaxel/L-NMMA combination resulted in a more significant anti-tumor effect in HFD mice, likely through remodeling of TME. Spatial analysis, including CODEX and immunophenotyping are being conducted to determine the TME influence in obesity associated TNBC and the effect of NOS inhibition.
Preclinical
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HER-2 (Human epidermal growth factor receptor 2) • PGR (Progesterone receptor) • IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • IL1B (Interleukin 1, beta)
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docetaxel • tilarginine (L-NMMA)
over1year
Elevated iNOS and 3'-nitrotyrosine in Kaposi's Sarcoma tumors and mouse model. (PubMed, Tumour Virus Res)
L-NMMA treatment reduced KSHV gene expression and perturbed cellular gene pathways relating to oxidative phosphorylation and mitochondrial dysfunction. These finding suggest that iNOS is expressed in KSHV infected endothelial-transformed tumor cells in KS, that iNOS expression depends on tumor microenvironment stress conditions, and that iNOS enzymatic activity contributes to KS tumor growth.
Preclinical • Journal
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NOS2 (Nitric Oxide Synthase 2)
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tilarginine (L-NMMA)
almost2years
Alpelisib/iNOS Inhibitor/Nab-paclitaxel in Patients With HER2 Negative Metaplastic Breast Cancer (MpBC) (clinicaltrials.gov)
P2, N=36, Recruiting, The Methodist Hospital Research Institute | Not yet recruiting --> Recruiting
Enrollment open • Metastases
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HER-2 (Human epidermal growth factor receptor 2) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
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HER-2 negative • PIK3CA mutation • PIK3CA E545 • PIK3CA E542
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Piqray (alpelisib) • albumin-bound paclitaxel • tilarginine (L-NMMA)
almost2years
New P2 trial
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HER-2 (Human epidermal growth factor receptor 2) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
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HER-2 negative • PIK3CA mutation • PIK3CA E545 • PIK3CA E542
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Piqray (alpelisib) • albumin-bound paclitaxel • tilarginine (L-NMMA)