TR57 / Madera Therap - LARVOL DELTA

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

The Application of Small Molecule ClpP Agonists as Novel Anti-Cancer Agents (EORTC-NCI-AACR 2024) - "Background The imipridones are a promising new class of anti-cancer compounds exemplified by ONC201 which is in multiple clinical trials including a Phase III trial for H3K27M glioma...In other studies, the TR compound (TR57) induced increases in cell surface protein expression and MHCI-associated peptides were identified and characterized by MS...This includes effects on cancer cell metabolism, morphology, senescence and cell surface immunoreactivity. Current goals are to determine if these events can be leveraged to improve the anti-cancer responses to these compounds through combinatorial application of senolytics or immune therapies."

Brain Cancer • Breast Cancer • CNS Tumor • Glioma • Head and Neck Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

TR-107, A NOVEL CLPP AGONIST, INHIBITS PANCREATIC CANCER IN VITRO (DDW 2024) - "Madera Therapeutics developed a family of novel ClpP activators including TR- 7 TR-57 TR-65 and TR-107... TR-107 inhibits PDAC viability through targeted dysregulation of the ClpXP complex and subsequent mitochondrial dysfunction in vitro ."

Preclinical • Gastrointestinal Cancer • Hepatology • Metabolic Disorders • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CLPP

The CIpP activator, TR-57, is highly effective as a single agent and in combination with venetoclax against CLL cells in vitro. (PubMed, Leuk Lymphoma) - "Despite advances in treatment, a significant proportion of patients with chronic lymphocytic leukemia (CLL) will relapse with drug-resistant disease.The imipridones, ONC-201 and ONC-212, are effective against a range of different cancers, including acute myeloid leukemia (AML) and tumors of the brain, breast, and prostate. These drugs induce cell death through activation of the mitochondrial protease, caseinolytic protease (CIpP), and the unfolded protein response (UPR).Here we demonstrate that the novel imipridone analog, TR-57, has efficacy as a single agent and synergises with venetoclax against CLL cells under in vitro conditions that mimic the tumor microenvironment. Changes in protein expression suggest TR-57 activates the UPR, inhibits the AKT and ERK1/2 pathways and induces pro-apoptotic changes in the expression of proteins of the BCL-2 family.The study suggests that TR-57, as a single agent and in combination with venetoclax, may represent an effective..."

Combination therapy • IO biomarker • Journal • Preclinical • Acute Myelogenous Leukemia • Brain Cancer • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2

Multi-omics analyses reveal ClpP activators disrupt essential mitochondrial pathways in triple-negative breast cancer. (PubMed, Front Pharmacol) - "Further analysis identified multiple pathways that were specifically impacted by ClpP activation, including ATF4 activation, heme biosynthesis, and the citrulline/urea cycle. In summary the results of our studies demonstrate that ONC201 and TR-57 induce highly similar and broad effects against multiple mitochondrial processes required for cell proliferation."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ATF4