TR-107 / Madera Therap - LARVOL DELTA

Targeting mitochondrial protease in diffuse gliomas. (PubMed, Mol Cancer Ther) - "Compared to the FDA-approved ClpP agonist ONC201 (Dordaviprone), TR107 shows greater efficacy across patient-derived and isogenic glioma models...In this study, we show that ClpP agonism demonstrates preferential anti-tumor activity against IDH-mutant glioma in in vitro, ex vivo, and in vivo models. These findings support TR107 as a promising new targeted therapeutic for IDH-mutant gliomas."

Journal • Brain Cancer • Glioma • Metabolic Disorders • Oncology • Solid Tumor • Targeted Protein Degradation • EIF4EBP1

Dordaviprone (ONC201) treatment generates canonical and non-canonical antigens that can be exploited for immunotherapy targets in diffuse midline glioma (ISPNO 2026) - "However, the identity and immunogenic relevance of drug-induced DMG antigens remain undefined.Here, we employed immunopeptidomics to characterise the human leukocyte antigen class I (HLA-I)–bound peptide repertoire following treatment of DMG cells with ONC201 and the related imipridones ONC206 and TR107...In summary, dordaviprone and related imipridones reprogram the DMG antigen landscape by expanding both canonical and non-canonical tumour peptides. These findings establish a mechanistic and translational framework for exploiting drug-induced antigen presentation to enable personalised immunotherapy for DMG."

IO biomarker • Brain Cancer • Diffuse Midline Glioma • Glioma • Solid Tumor • SDHA

Small molecule activators of the mitochondrial protease ClpP induce senescence in triple-negative breast cancer cells and sensitize cells to the Bcl-2 inhibitor venetoclax. (PubMed, Cell Death Dis) - "We report that ONC201 and highly potent second generation ClpP agonists (TR-57, TR-107), promote induction of senescence in triple-negative breast cancer (TNBC) cell lines...Finally, the combination of a ClpP agonist with a known senolytic (venetoclax), synergistically increased the amount of cell death observed. In summary, we show that ClpP agonists stably induce an irreversible senescence in a ClpP-dependent manner that synergizes with venetoclax in TNBC cells."

Journal • Breast Cancer • Metabolic Disorders • Oncology • Solid Tumor • Triple Negative Breast Cancer • CHEK2 • LMNB1 • MYC • TP53BP1

TR-107, a novel mitochondrial ClpP activator, exhibits potent antitumor activity in adrenocortical carcinoma models (AACR 2026) - "Collectively, these findings identify mitochondrial ClpP activation as a promising therapeutic strategy for ACC and demonstrate that TR-107 exerts potent antitumor activity as a monotherapy or in combination with IGF-1R blockade. These results provide strong preclinical support for advancing ClpP agonists toward clinical development for the treatment of ACC."

Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • ANXA5 • IGF2

TR-107 and erastin produce synergistic inhibition of colorectal cancer cell viability in vitro (AACR 2024) - "In vitro results suggest that co-treating with TR-107 and Erastin produces a significant, synergistic reduction in CRC cell viability."

Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • GPX4 • TFAM

Combination of the ClpP agonist TR107 and the MCL1 inhibitor MIK665 enhances cytotoxicity in breast cancer cells [WITHDRAWN] (AACR 2025) - "Ongoing work involves testing the combination in vivo and investigating specific biomarkers that predict cell line sensitivity to the drug combination. In summary, we found strongly additive or synergistic therapeutic efficacy of a treatment combining TR-107 and MIK665 in multiple breast cancer cell lines."

IO biomarker • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hematological Malignancies • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Leukemia • Oncology • Solid Tumor • Triple Negative Breast Cancer • BCL2 • CLPP • ER • HER-2 • PGR

Synthesis and Pharmacological Evaluation of Novel 1,5-Disubstituted-3-amino-1,2,4-triazoles Designed as Multitarget Directed Ligands for Alzheimer's Disease Targets. (PubMed, ACS Omega) - "Electron-withdrawing groups in R1 and R2 favorize PAS interactions that seem to guide efficient CAS interactions, mainly with residue Trp86 in AChE and Trp107 in BChE. Metal-binding studies showed intrinsic complexation of Cu2+ and Fe3+ for the 3-amino-1,2,4-triazole compounds, which could be expanded to other metals by specific structural modifications in ortho-position of R1 substituent. Selected derivatives also demonstrated low toxicity and protective antioxidant effects in Saccharomyces cerevisiae, significantly reducing lipid peroxidation."

Journal • Alzheimer's Disease • CNS Disorders • Pain

Small Molecule Activators of the Mitochondrial Protease ClpP Induce Senescence in Triple-Negative Breast Cancer Cells and Sensitize Cells to the Bcl-2 Inhibitor Venetoclax. (PubMed, Res Sq) - "We report that ONC201 and highly potent second generation ClpP agonists (TR-57, TR-107), promote induction of senescence in triple-negative breast cancer (TNBC) cell lines...By contrast, cells treated with the cell cycle inhibitor and senescence inducer, abemaciclib rapidly regained p-Rb and Myc expression and cell proliferation following washout...Combining a ClpP agonist with a PARP inhibitor (olaparib) produced an additive effect. In summary, we show that ClpP activators stably induce an irreversible senescence in a ClpP-dependent manner that synergizes with venetoclax in TNBC cells."

IO biomarker • Journal • Breast Cancer • Metabolic Disorders • Oncology • Solid Tumor • Triple Negative Breast Cancer • CHEK2 • LMNB1 • MYC • TP53BP1

Integrated multi-omics study identifies ursolic acid as a novel therapeutic agent targeting the TNF-α/TAK1/IKKβ/NF-κB axis in hepatic sinusoidal obstruction syndrome (ASH 2025) - "The busulfan-cyclophosphamide (BUCY)conditioning regimen induces endothelial injury, thereby initiating a thromboinflammatory cascade.While TNF-α/NF-κB signaling is implicated in this process, its precise role and therapeutic targeting in SOSremain undefined...In vitro: Primary rat HSECswere treated with BUCY ± UA, NF-κB was overexpressed (OE-p65 plasmid) or inhibited (BAY 11-7082).Apoptosis (Annexin V/PI flow cytometry), ROS (DCFH-DA), mRNA (qPCR), and protein (WB) levels of TNF-α/NF-κB pathway components and antioxidants were measured...MD simulations revealed stable binding of BUCYmetabolites (e.g., acrolein, ΔG=-8.2 kcal/mol) and UA to TNF-α (Tyr59/Trp107, ΔG=-9.3 kcal/mol)... TNF-α/NF-κB signaling critically drives BUCY-induced HSEC injury and SOS. UA, a first-in-classnatural TNF-α inhibitor, binds TNF-α with high affinity, thereby blocking downstream TAK1/IKKβ/NF-κBactivation. This mechanism suppresses endothelial inflammation, oxidative stress, and..."

IO biomarker • Bone Marrow Transplantation • Hepatology • Inflammation • ANXA5 • BAX • BCL2 • CASP3 • FASLG • ICAM1 • IL1B • IL6 • MMP9 • NFKBIA • RELA • TNFA • VCAM1

TR-107 MODULATES THE INFLAMMATORY PHENOTYPE OF PANCREATIC CANCER AND MAINTAINS EFFICACY AGAINST ORGANOIDS IN HYPOXIC CONDITIONS (DDW 2025) - "TR-107 maintains efficacy in PDAC cell lines and organoids in hypoxia. TR-107 treatment may modulate the hypoxic and/or inflammatory phenotype of PDAC, as evidenced by decreased HIF-1α levels and immune chemokine results of the inflammatory PCR array post-treatment. This alteration may ultimately translate to decreased tumor viability and sensitivity to chemotherapeutics."

Clinical • Oncology • Pancreatic Cancer • Solid Tumor • Targeted Protein Degradation • CLPP • CXCL10 • CXCL11 • HIF1A • TFAM