JZP3507 / Jazz - LARVOL DELTA

Combinatorial targeting of avapritinib-driven MAPK activation in pediatric high-grade glioma (SNO 2025) - "Combinatorial treatment of pHGG models with MEK (selumetinib, trametinib), ERK (ulixertinib) and integrated stress/ERK inhibitors (ONC201, ONC206) in vitro eradicated pERK activity. A patient with an un-resected PDGFRα-mutant pHGG treated with avapritinib and selumetinib prior to progression demonstrated complete and ongoing tumor regression (12 months+). Considering sustained MAPK activation identified in our study, dual avapritinib-MAPK targeted treatment may be an effective approach for PDGFRΑ-driven pHGG."

Clinical • Brain Cancer • CNS Tumor • Glioma • High Grade Glioma • Pediatrics • Solid Tumor • MCL1 • PDGFRA

An agonist of mitochondrial CLPP, ONC206, overcomes mitochondrial dependencies and abates chemoresistance in triple negative breast cancer (SABCS 2025) - P1, P2 | "Approximately 50% of triple-negative breast cancer (TNBC) patients treated with neoadjuvant chemotherapy such as platinums (e.g., carboplatin, CRB), taxanes (e.g., docetaxel, DTX), and anthracyclines administered alone, in combination, sequentially, or with or without anti-PD1 agents, retain residual cancer burden (RCB)...ONC206, an analog of the first-in-class imipridone/dordaviprone/ONC201 with improved potency, is currently undergoing phase I clinical trials for CNS tumors (NCT04732065 and NCT04541082)...Collectively, our findings provide evidence that ONC206 disrupts mitochondrial dependencies in TNBC by driving excessive CLPP-mediated proteolysis, impairing OXPHOS, and activating mtUPR. This represents a novel and potentially promising therapeutic strategy to enhance chemotherapy response in TNBC."

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

Allosteric ClpP agonist ONC206 alters mitochondrial metabolism and stress response to elicit apoptosis in meningioma (SNO 2025) - "Imipridone ONC206, a derivative of dordaviprone (ONC201) with nanomolar potency, is an allosteric caseinolytic protease P (ClpP) agonist and dopamine receptor D2/3 (DRD2/3) antagonist, that is being evaluated in clinical trials that include central nervous system tumors...ONC206 also demonstrated superior potency in cell viability inhibition compared to sunitinib at equivalent concentrations...CRISPR/Cas9-mediated knockout of ClpP abrogates ONC206 sensitivity in meningioma cells and ONC206 effects on mitochondrial respiratory capacity. Our results indicate that ClpP agonism is directly involved in mediating the anti-cancer effects of potent novel agent ONC206 in meningioma."

Brain Cancer • CNS Tumor • Meningioma • Solid Tumor • ANXA5 • DRD2

ONC206 inhibits tumor growth and is a potential novel therapeutic strategy for refractory medulloblastoma (SNO 2025) - P1 | "Dordaviprone (ONC201) and its chemical derivative with nanomolar potency ONC206 induce apoptosis of cancer cells by activation of the mitochondrial caseinolytic protease P (ClpP). PDX-bearing mice also responded to ONC206, which led to a significant survival benefit (p-value range 0.003-0.047). Our results highlight ONC206 as a novel therapeutic option for patients with relapsed medulloblastoma and importantly, our results have paced the way for a clinical trial testing the efficacy of ONC206 in recurrent malignant brain tumors, including medulloblastoma (NCT04732065, PNOC23)."

Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • ATF4 • CLPP

Combinatorial targeting of avapritinib-driven MAPK activation in pediatric high-grade glioma (WFNOS 2025) - "Combinatorial treatment of pHGG models with MEK (selumetinib, trametinib), ERK (ulixertinib) and integrated stress/ERK inhibitors (ONC201, ONC206) in vitro eradicated pERK activity. A patient with an un-resected PDGFRα-mutant pHGG treated with avapritinib and selumetinib prior to progression demonstrated complete and ongoing tumor regression (12 months+). Considering sustained MAPK activation identified in our study, dual avapritinib-MAPK targeted treatment may be an effective approach for PDGFRΑ-driven pHGG."

Clinical • Brain Cancer • CNS Tumor • Glioma • High Grade Glioma • Pediatrics • Solid Tumor • MCL1 • PDGFRA

Combinatorial targeting of avapritinib-driven MAPK activation in pediatric high-grade glioma (WFNOS 2025) - "Combinatorial treatment of pHGG models with MEK (selumetinib, trametinib), ERK (ulixertinib) and integrated stress/ERK inhibitors (ONC201, ONC206) in vitro eradicated pERK activity. A patient with an un-resected PDGFRα-mutant pHGG treated with avapritinib and selumetinib prior to progression demonstrated complete and ongoing tumor regression (12 months+). Considering sustained MAPK activation identified in our study, dual avapritinib-MAPK targeted treatment may be an effective approach for PDGFRΑ-driven pHGG."

Clinical • Brain Cancer • Pediatrics • Solid Tumor • MCL1 • PDGFRA

ONC206 demonstrates potent anti-tumorigenic activity and is a potential novel therapeutic strategy for high-risk medulloblastoma. (PubMed, bioRxiv) - P1 | "Dordaviprone (ONC201) and its chemical derivative with nanomolar potency, ONC206, induce apoptosis of cancer cells by activation of the mitochondrial caseinolytic protease P (ClpP). We also saw that ONC206 very significantly prolonged survival of medulloblastoma-bearing mice, both in genetically engineered mouse models and patient-derived xenografts. Our study provides a strong rationale for testing the efficacy of ONC206 in the treatment of patients with medulloblastoma and has set the stage for a clinical trial with this agent in pediatric patients with recurrent malignant brain tumors, including medulloblastoma ( NCT04732065 )."

Journal • Brain Cancer • Diffuse Midline Glioma • Glioma • Medulloblastoma • Oncology • Pediatrics • Solid Tumor • CLPP

Allosteric ClpP agonist ONC206 alters mitochondrial metabolism and stress response to elicit apoptosis in meningioma (WFNOS 2025) - "Imipridone ONC206, a derivative of dordaviprone (ONC201) with nanomolar potency, is an allosteric caseinolytic protease P (ClpP) agonist and dopamine receptor D2/3 (DRD2/3) antagonist, that is being evaluated in clinical trials that include central nervous system tumors...ONC206 also demonstrated superior potency in cell viability inhibition compared to sunitinib at equivalent concentrations...CRISPR/Cas9-mediated knockout of ClpP abrogates ONC206 sensitivity in meningioma cells and ONC206 effects on mitochondrial respiratory capacity. Our results indicate that ClpP agonism is directly involved in mediating the anti-cancer effects of potent novel agent ONC206 in meningioma."

Brain Cancer • Meningioma • Solid Tumor • ANXA5 • DRD2

ONC206 inhibits tumor growth and is a potential novel therapeutic strategy for refractory medulloblastoma (WFNOS 2025) - P1 | "Dordaviprone (ONC201) and its chemical derivative with nanomolar potency ONC206 induce apoptosis of cancer cells by activation of the mitochondrial caseinolytic protease P (ClpP). PDX-bearing mice also responded to ONC206, which led to a significant survival benefit (p-value range 0.003-0.047). Our results highlight ONC206 as a novel therapeutic option for patients with relapsed medulloblastoma and importantly, our results have paced the way for a clinical trial testing the efficacy of ONC206 in recurrent malignant brain tumors, including medulloblastoma (NCT04732065, PNOC23)."

Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • ATF4 • CLPP

Jazz Pharmaceuticals Showcases New Clinical and Translational Data for Modeyso (dordaviprone) in H3 K27M-mutant Diffuse Midline Glioma at SNO 2025 (PRNewswire) - "The presentations will feature both clinical and preclinical research evaluating Modeyso (dordaviprone), as well as new preclinical data featuring JZP3507 (formerly ONC206) in central nervous system (CNS) tumors....Key presentations include: (i) New translational research characterizing potential molecular pathways associated with sensitivity to dordaviprone and exploring how targeted combination strategies may help to enhance response; (ii) Preclinical data evaluating how dordaviprone may influence the tumor immune environment to inform future research on rational immunotherapy combinations."

Clinical data • Preclinical • Diffuse Midline Glioma

IMIPRIDONES ONC201/ONC206 AND RADIOTHERAPY REMODEL THE TUMOR-IMMUNE MICROENVIRONMENT IN DIFFUSE MIDLINE GLIOMAS (SIOP 2025) - "However, the rise in Tregs under combination therapy suggests a compensatory immunosuppressive response. These findings highlight the urgent need to recognize how standard treatments like chemotherapy and RT can unintentionally undermine anti-tumor immunity—emphasizing the importance of integrating immunomodulatory strategies into future therapeutic approaches for DMG."

Brain Cancer • CNS Disorders • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • PTPRC

Allosteric ClpP agonist ONC206 alters mitochondrial metabolism, stress response and chromatin accessibility to elicit apoptosis in pheochromocytoma (NANETS 2025) - "ONC206 demonstrated superior cell viability inhibition and/ or apoptosis induction in PC lines relative to dordaviprone, temozolomide, sunitinib and belzutifan at equivalent and/or therapeutically relevant concentrations. CONCLUSIONS ONC206 is a potent novel agent that is superior to SOC and dordaviprone in PC. ClpP mediates response and acquired resistance to ONC206 in PC."

Oncology • Solid Tumor • ANXA5 • CLPP • DRD2 • SDHB

Trial-in-Progress: A Phase 2 Study of ONC206 in Patients with Advanced Pheochromocytoma and Paraganglioma (NANETS 2025) - "This small molecule is a potent derivative of dordaviprone that was previously reported to induce responses in patients with PCPG. Total anticipated enrollment is 90 patients. RESULTS N/A CONCLUSIONS N/A"

Clinical • Metastases • P2 data • CNS Tumor • Oncology • Solid Tumor • DRD2

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

Preclinical efficacy of combinatorial B7-H3 CAR T cells and ONC206 against diffuse intrinsic pontine glioma. (PubMed, bioRxiv) - P1 | "This work offers a biologically-informed, clinically translatable strategy integrating small molecule therapeutics with CAR T cell therapy and support the development of multi-agent immunotherapy trials for children with DIPG and other high-grade brain and spinal cord tumors. B7-H3 CAR T cells are cytotoxic against preclinical DMG models.ONC206 causes metabolic apoptosis in preclinical DMG models.B7-H3 CAR T cells and ONC206 have combinatorial efficacy against DMG."

Journal • Preclinical • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Hematological Disorders • Hematological Malignancies • Metabolic Disorders • Oncology • Pediatrics • Solid Tumor • CD276 • GZMB • IFNL1 • IL2

ONC206 as a low-potency dopamine D2 receptor antagonist. (PubMed, Neurooncol Adv) - No abstract available

Journal • DRD2

Investigating the Effects of ONC206 Alone and in Combination with Cisplatin on Ovarian Cancer Cell Models. (PubMed, Curr Issues Mol Biol) - "Our results highly suggest the potential of imipridones as a new class of therapeutics in ovarian cancer management. Among these, ONC206 shows nanomolar potency, highlighting its potential as a standalone therapy or in combination with existing treatment regimens."

Journal • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

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

Precision oncology in pediatric brain tumors: Real world experience from a middle income country. (ASCO 2025) - "Agents used included dabrafenib+trametinib (3), trametinib(3), bevacizumab (17), nimotuzumab (5), everolimus (1),ONC201 (2), ONC206 (1). Our experience with biologically targeted therapies in RR CNS tumors was promising with manageable toxicities. Further studies could explore TT in earlier treatment lines and/or as maintenance therapy."

Clinical • Real-world • Real-world evidence • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • Diffuse Midline Glioma • Glioma • High Grade Glioma • Medulloblastoma • Oncology • Pediatrics • Solid Tumor • BRAF • EZH2 • KIAA1549 • NF1 • NTRK

Combination therapy of supercharged NK cells and ONC201 or ONC206 to target aggressive K27M brain tumor. (PubMed, Crit Rev Immunol) - "sNK cell-mediated cytotoxicity against K27M was significantly increased when sNK cells were combined with ONC201 and ONC206. This study suggests the potential use of sNK cells alone or in combination with ONC201 or ONC206 as therapeutic strategies in treating and preventing the recurrence of aggressive pediatric brain tumors."

Journal • Review • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Glioma • High Grade Glioma • Oncology • Pediatrics • Solid Tumor • IFNG

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

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

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 • Malignant Glioma • Oncology • Solid Tumor • MGMT

Tumor treating fields with imipridone ONC206 in murine model of colorectal cancer [WITHDRAWN] (AACR 2025) - "Our ongoing studies further explore the effect of synergy on common pathways. Our results suggest an effective novel combination of Imipridone ONC206 and TTFields for the treatment of colorectal cancer."

Preclinical • Brain Cancer • CNS Tumor • Colorectal Cancer • Glioblastoma • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ATF4 • DRD2

Dopamine receptor D2 and dopamine antagonism modulate the progression of small cell lung cancer (AACR 2025) - "To assess the therapeutic potential of DRD2, we utilized ONC206, a highly specific, orally bioavailable, and blood-brain barrier penetrating DRD2 antagonist...Integrated gene expression studies coupled with pathway analysis showed that DRD2 inhibition reduces SCLC growth and metastasis by inhibiting the cholesterol biosynthesis pathway. Altogether, our study provides strong preclinical rationale for targeting DRD2 via dopamine antagonism to attenuate SCLC growth and metastasis."

IO biomarker • Brain Cancer • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • DRD2