JZP3508 / Jazz - LARVOL DELTA

KATP Channel Expression Determines ONC212 Sensitivity via Mitochondrial Dysfunction and PERK/ATF4/CHOP Activation in Glioblastoma. (PubMed, J Cell Mol Med) - "KATP was modulated pharmacologically (glibenclamide, diazoxide) and via KCNJ11 (Kir6.2) siRNA. KATP channel expression may regulate ONC212 responsiveness in GBM by modulating mitochondrial stress and ISR signalling. Targeting KATP channels may enhance imipridone efficacy and represents a promising strategy for metabolically guided GBM therapy."

Journal • Brain Cancer • Glioblastoma • Metabolic Disorders • Oncology • Solid Tumor • ATF4 • CASP3 • CASP7 • KCNJ11

Preclinical Evaluation of Novel Imipridones: Potent and Selective Antitumor Activity In Vitro and In Vivo (EACR 2026) - "Parallel development of ONC-212 is ongoing... Novel imipridones display strong antiproliferative activity and cancer selectivity in vitro, while FRE-265 demonstrates the most favorable balance between efficacy and safety in vivo, supporting its further development as a promising anticancer candidate."

Preclinical • Brain Cancer • Breast Cancer • Glioma • High Grade Glioma • Oncology • Oral Cancer • Pancreatic Cancer • Solid Tumor • Triple Negative Breast Cancer

Integrated Phenotypic and Transcriptomic Profiling Positions ONC212 as a Lead Imipridone in Androgen-Independent Prostate Cancer Models. (PubMed, Int J Mol Sci) - "DU145 and PC3 AIPC cells were treated with ONC201 (parent compound), ONC206, or ONC212...Imipridones induced a time-dependent cell-cycle redistribution with increased sub-G1 accumulation and modulated mitochondrial membrane potential and mass in a context-dependent manner. Collectively, these findings position ONC212 as a leading imipridone candidate in AIPC models, combining potent inhibition of tumor and stem-like cell functions with a coherent stress-response signature that supports further translational evaluation."

Journal • Preclinical • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ATF4

Imipridones ONC201, ONC206, and ONC212 show potent killing and colony arrest of small-cell lung cancer cell lines (AACR 2026) - "The present findings suggest that SCLC may be highly sensitive to imipridones, particularly ONC212. Future works will aim to explore combination therapies and potential mechanisms including senescence induction, cell cycle alterations that may lead to reproductive arrest, metabolic changes, and alterations in growth and survival pathways in order to further characterize sensitivity and the colony arrest phenotype."

Preclinical • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ATF4

Determining mechanisms of ONC212-resistance in uveal melanoma to develop combination therapy strategies (AACR 2026) - "ONC212-resistant clones exhibited higher IC50, and RI compared to parental cells and showed cross-resistance to other imipridones (ONC201, ONC206), suggesting shared mechanisms of resistance...Importantly, ONC201, the first imipridone was recently approved for therapy of midline gliomas. Therefore, lessons learned from this study may benefit patients acquiring resistance to ONC201 in future as well."

Combination therapy • Brain Cancer • Eye Cancer • Glioma • Melanoma • Ocular Melanoma • Oncology • Solid Tumor • Uveal Melanoma

Imipridone treatment activates canonical NFkB and inflammatory signaling in THP1 differentiated macrophages (IMMUNOLOGY 2026) - "Following differentiation, we treated the cells with 5µM or 2µM ONC201, 1.5µM or 0.75µM ONC206, or 0.1µM or 0.05µM ONC212 and collected lysates for western blot. Using the hallmarks gene set, we found that increased expression of genes associated with a baseline inflammatory, IFNα and IFNγ response were associated with patient radiographic response... We have identified a link between a more immunologically active TME and response to ONC201 in patients with DMG, and that changes in NFkB signaling occurred following imipridone treatment of the THP1 cell line. We will continue our analysis of changes in cytokine production through ELISA and luciferase reporter assays."

Brain Cancer • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioma • High Grade Glioma • Solid Tumor • ATF4 • GLI2 • IFNA1 • IFNG • IL1B • NLRP3

Reduced severity of radiation esophagitis in mice following 2 weeks of ONC212 treatment [WITHDRAWN] (AACR 2025) - "Our results provide a strategy with an orally bioavailable drug for treatment of severe esophagitis that is caused by therapeutic radiotherapy involving the esophagus. Additional directions for future research include studies of other TRAIL pathway agonists such as TRAIL itself, TLY012, or other imipridones including ONC201 or ONC206 effects on severity of radiation esophagitis."

Preclinical • Breast Cancer • Esophageal Cancer • Head and Neck Cancer • Lung Cancer • Oncology • Solid Tumor • CCL2 • CCL22 • CCL3 • CXCL12 • EGF • IGF1 • IL16

Preclinical analysis of ONC206 and ONC212 with lurbinectedin in pancreatic cancer (AACR 2025) - "Our group recently described lurbinectedin's potency as both a single agent and combinatorial agent with irinotecan and 5-fluorouracil in pancreatic cancer cell lines...Future studies will analyze whether a combination of lurbinectedin and ONC212 or lurbinectedin and ONC206, another imipridone and chemical analogue of ONC201, proves more efficient at killing pancreatic tumor cells in vitro. Our results are developing insights into novel combinatorial therapeutic regimens while investigating the molecular mechanisms underlying synergism."

Preclinical • Lung Cancer • Oncology • Pancreatic Cancer • Small Cell Lung Cancer • Solid Tumor

Imipridones ONC201, ONC206, and ONC212 promote immune-mediated cell death and anti-tumor activity in biliary tract cancer models in vitro (AACR 2025) - "Imipridones and MEK inhibitors exhibit potent antineoplastic effects in BTC cell lines. In RBE cells, half maximal inhibitory concentrations (IC50) were 2.53 μM (ONC201), 917 nM (ONC206), 46.99 nM (ONC212), and 5.94 μM (trametinib), while in HuCCT1 cells, they were 1.97 μM (ONC201), 1.06 μM (ONC206), 38.95 nM (ONC212), and 3.71 μM (trametinib). Imipridones (ONC201 and ONC212) with trametinib showed synergy in HuCCT1 cells."

Preclinical • Biliary Cancer • Biliary Tract Cancer • Oncology • Solid Tumor • DRD2

Pre-clinical efficacy of tumor treating fields and imipridones in glioblastoma and colorectal cancer cell lines (AACR 2025) - "We then treated cells with imipridones at the identified IC50 doses either alone or together with 200kHz TTFields and collected cell lysate after 72 hours.We found differences in AKT phosphorylation across our treatment conditions (control, ONC201, ONC206, ONC212, TTF, TTF + ONC201, TTF + ONC206, and TTF + ONC212). These findings are significant in guiding future in vivo experiments and offering insight on whether TTField and imipridone treatment can be further explored in clinical trials."

Preclinical • Brain Cancer • CNS Tumor • Colorectal Cancer • Glioblastoma • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Imipridones (ONC201, ONC206 and ONC212) modulate MGMT and ClpX expression in DIPG cell lines (AACR 2025) - "Temozolomide (TMZ) is an oral alkylating agent that is generally well tolerated. We are going to test this mechanism of synergy and therapeutic efficacy in vivo by treating orthotopic DIPG mouse models with imipridones -/+ TMZ. Our results support further studies combining imipridones (ONC201, ONC206 and ONC212) with TMZ and RT as a reasonable and safe therapeutic option for DIPG."

Preclinical • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioblastoma • Glioma • High Grade Glioma • Oncology • Solid Tumor • MGMT

TRAIL-inducing imipridones ONC201, ONC206, and ONC212 demonstrate anti-neoplastic effects in colonic adenoma-derived organoids (AACR 2025) - "ONC206 and ONC212 demonstrated antineoplastic effects on adenoma-derived FAP and SSA organoids, with half maximal inhibitory concentrations (IC50) less than that of ONC201 in FAP and SSA organoids. As was noted in ONC201 studies, the mechanism of action of ONC206 and ONC212 appears to be mediated through modulation of multiple pathways including the TRAIL pathway (TRAIL and DR5 upregulation) and the integrated stress responses (ATF4 upregulation). Co-culture with NK cells revealed a significant increase in NK-mediated organoid cell death."

Colorectal Cancer • Oncology • Solid Tumor • ATF4

Imipridones ONC201 and ONC212 exhibit anti-tumor activity in biliary tract cancers and synergy when combined with trametinib and olaparib in vitro (AACR 2024) - "Both ONC201 and ONC212 demonstrated antineoplastic effects in two BTC cell lines. Half maximal inhibitory concentrations (IC50) of ONC201 in RBE and HuCCT1 cell lines were 2.5uM and 2.0uM, respectively. The IC50 of ONC212 in RBE and HuCCT1 was 47nM and 39nM, respectively, which was similar to IC50s demonstrated with cytotoxic chemotherapy (gemcitabine IC50 = 7.57nM (RBE) and 9.84nM (HuCCT1))."

Preclinical • Biliary Cancer • Biliary Tract Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • DRD2

Synergistic combinations of lurbinectedin with ONC212 in pancreatic cancer (AACR 2024) - "Our group recently described lurbinectedin's potency as both a single agent and combinatorial agent with irinotecan and 5-fluorouracil in pancreatic cancer cell lines. We also recently discovered a synergistic interaction between lurbinectedin and ONC201/TIC10, a novel compound that induces the TRAIL apoptotic pathway, in small cell lung cancer cell lines...We further hypothesize a combination of lurbinectedin and ONC212 will sensitize the tumor cells to CD8+ T-cell killing, which will be examined via co-culture assays. Our results are developing insights into a novel combinatorial therapeutic regimen while investigating the molecular mechanisms underlying synergism."

Gastrointestinal Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Small Cell Lung Cancer • Solid Tumor • CD8 • CHEK1

The imipridone ONC212 cooperates with MEK and immune checkpoint inhibition to elicit in vivo regression in KPC T cell-low mouse pancreatic tumors [WITHDRAWN] (AACR 2025) - "We found that the combination of ONC212 and trametinib exhibited synergy in the T cell-low cell line in vitro. Our in vivo experiments revealed that, similar to the T cell-high cell line, the triple therapy containing ONC212, trametinib, and ICI (anti-PD-1 mAb) effectively slowed T cell-low tumor growth. However, differences were observed in these two KPC models."

Checkpoint inhibition • IO biomarker • Preclinical • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

The imipridone ONC212 cooperates with MEK and immune checkpoint inhibition to elicit in vivo regression of KPC mouse pancreatic tumors (AACR 2024) - "We found that the combination of ONC212 and trametinib exhibited synergy in the KPC cell line in vitro. Our in vivo experiments revealed that ONC212 controlled KPC tumor growth in a dose-dependent manner, however, toxicity was also noted at higher, more frequent doses. While both 25 mg/kg and 50 mg/kg twice weekly were equally effective, 25 mg/kg was better tolerated and determined to be the ideal dose."

Checkpoint inhibition • Preclinical • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

Enhancing chemotherapy efficacy in pancreatic cancer synergistic effects of ONC206 and ONC212 with 5-FU through inhibition of p-ERK (AACR 2025) - "Resistance to chemotherapy, particularly 5-fluorouracil (5-FU), remains a major challenge in treating pancreatic ductal adenocarcinoma (PDAC). Our data demonstrate that combining 5-FU with ONC206 or ONC212 results in the inhibition of p-ERK, a critical node in the PDAC growth pathway. This synergy between 5-FU and the imipridone compounds ONC206 and ONC212 is a universal phenomenon in the tested human PDAC cell lines. Notably, ONC212 is more potent than ONC206, allowing for lower dosages, and in cases where ONC206 does not effectively inhibit p-ERK, ONC212 can be a more effective option Further studies are needed to elucidate the exact mechanism of this synergy, but these findings provide a promising foundation for developing novel combination therapies to improve PDAC treatment outcomes."

Clinical • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • ATF4 • DRD2 • GPR132

Elraglusib (9-ING-41), a glycogen synthase kinase-3β inhibitor in combination with imipridones for treatment of solid cancer (AACR 2025) - "Ovarian, GBM, pancreatic, and colorectal cancer cell lines were treated with the novel drug combination of elraglusib and imipridone ONC206...In pancreatic and colorectal cancer cell lines, synergy was also investigated and observed between elraglusib and imipridone ONC212...Our ongoing studies are exploring other potential mechanisms of synergy and effects on immune-mediated killing of cancer cells. Our results show a potentially effective new combination of Elraglusib and Imipridones that can be further developed for cancer treatment."

Combination therapy • Brain Cancer • CNS Tumor • Colorectal Cancer • Glioblastoma • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • BIRC5 • MCL1 • RELA • TNFA • TNFRSF10B

Discovery and characterization of Z1: an imipridone-based ClpP agonist with potent anti-staphylococcal activity. (PubMed, Bioorg Chem) - "Quantitative analysis demonstrated that the activating potency EC50 of Z1 toward SaClpP is markedly superior to that of the clinical candidate ONC212...In a murine skin infection model, Z1 significantly reduced bacterial burden, diminished the infection area, and improved histopathological outcomes. These findings highlight Z1 as a promising ClpP agonist and support the strategy of targeting ClpP for the development of next-generation antibiotics."

Journal • Dermatology • Infectious Disease • Targeted Protein Degradation

Targeting the Mitochondrial Protease ClpP for Anticancer Therapy. (PubMed, J Med Chem) - "Furthermore, we show that compound 9 induced cell death in cancer cells resistant to ONC212. The discovery and characterization of compound 9 therefore add to the expanding arsenal of imipridones to target ClpP in cancer."

Journal • Breast Cancer • Oncology • Solid Tumor

Combination of the First-in-Class Imipridone ONC201 and Standard Anticancer Therapies as a Rational Approach for Therapeutic Benefit. (PubMed, Curr Issues Mol Biol) - "ONC206 and ONC212, are more potent analogs of ONC201 and exhibit similar characteristics. In this review, we discuss the therapeutic potential of ONC201 and its analogs using combination strategies across different cancers."

Journal • Review • Brain Cancer • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor

Discovery of SaClpP-Selective Imipridone Derivatives as Novel Antistaphylococcal Agents. (PubMed, J Med Chem) - "Based on ONC212, a previously reported activator of hClpP and SaClpP, a novel class of SaClpP-selective imipridones featuring a substituted group at C8 was designed, synthesized, and evaluated...Furthermore, it effectively promoted wound healing in a murine skin infection model using S. aureus American Type Culture Collection 25923. These findings underscore its promising therapeutic potential, along with its analogues, for the treatment of S. aureus infections."

Journal • Dermatology • Infectious Disease

Evaluation of the antineoplastic effects of imipridone derivatives in prostate cancer: Novel therapeutic opportunities (EACR 2025) - "However, the anticancer potential of its derivatives, ONC206 and ONC212, remains unexplored in the context of PCa. This study highlights ONC212 as a promising therapeutic candidate for targeting PCSCs, potentially improving PCa management by overcoming tumor resistance and recurrence."

Genito-urinary Cancer • Hematological Malignancies • Oncology • Prostate Cancer • Solid Tumor

Reduced EZH1/2 expression in imipridone-treated cells correlates with synergy following combinations with EZH1/2 or HDAC inhibitors in diffuse glioma and other tumors. (PubMed, Am J Cancer Res) - "Small molecule imipridones including ONC201, ONC206 and ONC212 have anti-cancer activity mediated in part through the integrated stress response, induction of TRAIL and its receptor DR5, and activation of mitochondrial caseinolytic protease ClpP with impaired oxidative phosphorylation...RNA-seq showed ONC201 and EHZ2i tazemetostat-treated cells have similar transcriptional profiles and share overlap of top regulated genes...ONC201 and EZH2i share similar targets and actions on tumors. Synergistic combinations of imipridones plus EZH1/2i or imipridones, EZH2i and HDACi merit further investigation."

Journal • Brain Cancer • Breast Cancer • CNS Tumor • Gastric Cancer • Gene Therapies • Genito-urinary Cancer • Glioma • Lung Cancer • Oncology • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor • EZH2

Discovery of novel seven-membered ring derivatives of ONC212 as caseinolytic protease P protein activators using the ring expansion strategy: Rational design, synthesis, and antibacterial evaluation. (PubMed, Int J Biol Macromol) - "In vivo assays showed that the control activity of compound A14 (200 μg/mL) reached 47.47 %, compared to 41.57 %, 36.72 %, and 30.43 % for ONC212, thiodiazole copper, and bismerthiazol, respectively. Overall, this study led to the identification compound A14, which not only showed improved antibacterial potency, and maintained the binding XooClpP, but also highlighted the ring expansion strategy as a promising approach for bactericide discovery."

Journal • Infectious Disease