nesuparib (JPI-547) / Jeil, Onconic Therapeutics - LARVOL DELTA

ONC201/dordaviprone for H3 K27M-mutant tumors: Discovery, mechanisms, therapeutic potential, and future directions. (PubMed, Genes Dis) - "Despite these advances, emerging resistance mechanisms, including ClpP mutations and adaptive activation of the EGFR and MAPK/AKT pathways, highlight the need for biomarker development and rational combination strategies. Together, these insights position ONC201 as both a therapeutic milestone and a platform for future translational oncology innovation."

Journal • Review • Brain Cancer • Diffuse Midline Glioma • Glioma • Gynecologic Cancers • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor • DRD2

Pharmacological inhibition of CD147 restrains tumor progression and remodels tumor-stroma crosstalk in H3K27-altered diffuse midline glioma (EANO 2026) - "Combination with ONC201 produced synergistic viability reduction... Overall, these findings identify BSG/CD147 as a key regulator of tumor growth and microenvironment architecture in DMG, supporting its inhibition as a promising therapeutic strategy."

Stroma • Brain Cancer • Diffuse Midline Glioma • Glioma • High Grade Glioma • Oncology • Solid Tumor • BSG • CASP3 • CASP9 • CD133 • CD163 • CD68 • CDKN1A • SOX2

Onconic Therapeutics…said on the 31st that it received a manufacturing patent in the United States for Nesuparib, which is being developed as an anticancer drug (Chosun Biz) - "Nesuparib is in clinical trials to allow prescriptions for patients with pancreatic, ovarian, endometrial, and stomach cancers. The substance patent for Nesuparib expires in 2036. The company separately secured a patent for a new crystal form of Nesuparib and its manufacturing method. The patent term is May 2042. The company said this will allow Nesuparib to be protected in the U.S. pharmaceutical market until then....The company plans to submit an investigational new drug (IND) application for a phase 2 trial of Nesuparib in the United States by the end of this year."

IND • New P2 trial • Patent • Endometrial Cancer • Gastric Cancer • Ovarian Cancer • Pancreatic Cancer

Design, Synthesis, and Structure-Activity Relationships of Novel Piperidine-Fused Imidazolone ClpP Activators as Potential Anti-Cancer Agents. (PubMed, Molecules) - "However, ONC201 is currently the only approved ClpP activator, and its low potency leads to high clinical doses, driving an urgent demand for highly potent agents...Furthermore, CLPP-3036 promotes the degradation of ClpP substrate proteins and effectively triggers apoptosis in MV4-11 cells. Collectively, CLPP-3036 is a potent piperidine-fused imidazolone ClpP activator and represents a promising lead compound worthy of further study."

Journal • Hematological Disorders • Oncology • Solid Tumor

ONC201 enhances the radiosensitivity of small-cell lung cancer via inhibition of the FAK signaling pathway. (PubMed, iScience) - "Mechanistically, we confirmed that ONC201 enhanced radiosensitivity by suppressing focal adhesion kinase (FAK) signaling. Overall, our findings underscore the potential of ONC201 as a promising radiosensitizer for SCLC treatment."

Journal • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

Disruption of mitochondrial protein import is a consequence of ClpP activator chemotherapeutics | Poster Board #1066 (ACS-Fall 2026) - "Activators of the mitochondrial matrix protease ClpP (ONC201, TR compounds) represent novel small molecule chemotherapeutics with efficacy in a wide variety of cancers...These data suggest that ClpP agonists disrupt PAM complex function, either directly or indirectly, resulting in sustained inhibition of mitochondrial protein import and function. This irreversible destabilization of mitochondrial proteostasis may set ClpP activators apart from existing therapies as an especially resilient line of treatment in the face of acquired drug resistance."

Brain Cancer • Breast Cancer • Diffuse Midline Glioma • Glioma • Solid Tumor • Triple Negative Breast Cancer • PHACTR1

Interplay of Epigenetic Reprogramming, Mitochondrial Metabolism, and Dopamine Signalling Pathways Uncovers Metabolic Vulnerabilities in Diffuse Midline Glioma. (PubMed, Cancers (Basel)) - "The imipridone compound ONC201/dordaviprone, initially described as a dopamine receptor D2/3 antagonist and subsequently characterised as a mitochondrial ClpP agonist, demonstrates clinical activity in H3K27M-mutant DMG and induces mitochondrial stress responses...Within this context, dopamine signalling may function as a metabolic rheostat that contributes to mitochondrial homeostasis; however, this remains a hypothesis requiring direct experimental validation in DMG models. Pharmacologic disruption of this axis may destabilise tumour metabolism and expose therapeutically exploitable vulnerabilities in this otherwise treatment-resistant disease."

Journal • Review • Brain Cancer • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • DRD2

The interplay between ONC 201 and Cisplatin in promoting cell death by modulating MET signaling through triggering the mitochondrial stress response in head and neck squamous cell carcinoma (AHNS 2026) - "The preliminary results indicate that ONC201 suppresses MET signaling and decreases the levels of anti-apoptotic proteins, leading to increased cell death. Targeting the MET pathway could be a potential new strategy for cancer patients, especially those with recurrent /metastatic HNSCC."

Head and Neck Cancer • Hematological Malignancies • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

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

Targeting dopamine receptor signalling and mitochondrial metabolism as a therapeutic approach for diffuse midline gliomas (ISPNO 2026) - "This dual targeting of dopamine signalling and mitochondrial metabolism mirrors the mechanism of action of ONC201, a leading therapeutic candidate for DMG currently in phase III clinical trials. Collectively, these findings suggest that targeting dopamine receptor signalling alongside mitochondrial metabolism represents a promising strategy to inhibit tumour growth and enhance radiotherapy efficacy in DMG. Ongoing studies aim to further define the underlying mechanisms, validate efficacy in preclinical DMG models, and optimise therapeutic approaches to support future clinical translation."

Brain Cancer • Diffuse Midline Glioma • Glioma • Solid Tumor

Drug-candidates targeting mitochondrial protease HsClpP developed for paediatric diffuse midline glioma/diffuse intrinsic pontine glioma treatment (ISPNO 2026) - "The identified THX6 and DA29 have a chemical structure different from ONC201, are HsClpP activators, and are highly cytotoxic in DIPG cell lines, capable to cross the blood-brain barrier, meaning they would penetrate the brain and reach the tumor area."

Brain Cancer • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioma • High Grade Glioma • Pediatrics • Solid Tumor • NRF1 • SDHA • TFAM

Leveraging the immunomodulatory effects of dordaviprone to induce tumor-immune surveillance in diffuse midline glioma (ISPNO 2026) - "In conclusion, this study shows dordaviprone drives DMG MHC-I expression and promotes infiltration of cytotoxic lymphocytes. Further, we identify immunosuppressive MDMs as a potential resistance mechanism, prompting continued investigation into possible combination strategies."

Immunomodulating • Brain Cancer • Diffuse Midline Glioma • Glioma • High Grade Glioma • Oncology • Solid Tumor • B2M • CD3E • CD4 • CD8 • PDGFRA • SPP1

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

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

An open-label, dose-finding, randomized phase II study evaluating the efficacy, safety, and pharmacokinetics of nesuparib (JPI-547) with bevacizumab maintenance in relapsed ovarian cancer patients previously treated with PARP inhibitors who responded to last platinum therapy (ESMO-Gynae 2026) - "Part B randomizes ∼60 patients (2:1) to nesuparib + bevacizumab vs bevacizumab alone, stratified by BRCA1/2 status and platinum response. The primary endpoint is 12-month PFS rate; secondary endpoints include PFS, PFS2, time to subsequent therapy, OS, and safety, with exploratory PD and antitumor activity."

Clinical • P2 data • PK/PD data • Fallopian Tube Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • BRCA • BRCA1 • BRCA2 • HRD

Targeting CD147 impairs tumor growth and alters microenvironmental spatial organization in H3 K27-altered diffuse midline glioma (EACR 2026) - "Proliferation, clonogenicity, and combination experiments with ONC201 were evaluated using functional assays... Collectively, these findings identify BSG as a key regulator of tumor growth and microenvironmental spatial organization in DMG, supporting its targeting as a promising therapeutic strategy for aggressive pediatric gliomas."

Brain Cancer • Diffuse Midline Glioma • Glioma • High Grade Glioma • Oncology • Solid Tumor • BSG • CASP3 • CASP9 • CD133 • CD163 • CD68 • CDKN1A • SOX2

ONC201 Plus Weekly Paclitaxel in Patients With Platinum Refractory or Resistant Ovarian Cancer (clinicaltrials.gov) - P2 | N=62 | Recruiting | Sponsor: Ira Winer | Trial primary completion date: May 2026 ➔ May 2027

Platinum resistant • Trial primary completion date • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Refractory Ovarian Cancer • Solid Tumor

Onconic Therapeutics said on the 25th that it is preparing to submit an investigational new drug application (IND) to the U.S. Food and Drug Administration (FDA) within the year to expand Nesuparib's phase 2 trial from Korea to a global study (Chosun Biz) - "Based on the ongoing phase 2 trial in Korea, the company plans to submit an FDA IND in the United States and expand into a global phase 2 that includes the U.S."

IND • New P2 trial • Solid Tumor

UPR/ATF4/Noxa pathway over-activation through SERCA2 inhibition or ONC201 treatment combined with ABT-737 triggers apoptosis in chemoresistant ovarian cancer cells and patient-derived tumor organoids (EACR 2026) - "Introduction: Ovarian cancer has a poor clinical prognosis due to chemoresistance following carboplatin/paclitaxel treatment...Material and The platinum-resistant cell line, OAW42-R, the HGSOC ovarian cell line OVCAR3 and patient-derived tumor organoids models (PDTO) were treated with anti-SERCA2 strategies (thapsigargin and siRNA targeting SERCA2) in presence of ABT-737.Result and Anti-SERCA2 strategies reverted the BCL-2 family member expression ratio in favour of pro-apoptotic proteins... Collectively, our study highlights that ABT 737, through BCL-xL inhibition and synergy with ER stress inducers, triggers ovarian cancer death, offering promising strategies for overcoming chemoresistance in relapsed ovarian cancer."

Clinical • IO biomarker • Oncology • Ovarian Cancer • Solid Tumor • ATF4 • BCL2 • BCL2L1

Dual PARP/Tankyrase Inhibition Enhances Antitumor Efficacy in PTEN-Deficient Endometrial Cancer. (PubMed, J Cell Mol Med) - "In vitro, JPI-547 and olaparib more effectively reduced cell survival in PTEN-deficient cells, and combined treatment with olaparib and the TNKS inhibitor XAV-939 induced synergistic cytotoxicity with elevated DNA double-strand breaks. PTEN knockdown further showed enhanced vulnerability to combined targeting. These findings show that JPI-547 enhances antitumor efficacy in PTEN-deficient EC by disrupting DNA repair pathways and Wnt signalling, supporting dual PARP/TNKS inhibition as a potential therapeutic strategy and providing a rationale for further clinical evaluation."

Journal • Endometrial Cancer • Oncology • Solid Tumor • BRCA • PTEN • RAD51

Tumor extracellular vesicle RNA profiling predicts treatment response in pediatric diffuse midline glioma. (PubMed, bioRxiv) - "EV H3K27M mRNA enabled discrimination of DMG from non-DMG controls, and exploratory EV response-associated mRNAs were linked to radiographic response and progression-free survival in patients receiving ONC201. To enable tumor-selective EV enrichment and multiplexed molecular profiling within a clinically practical workflow, we developed a new integrated platform supporting same-day EV analysis from small plasma volumes. This work represents the first proof-of-concept demonstration of the diagnostic and treatment response relevance of tumor-derived EV RNA in pediatric DMG and establishes a generalizable framework for minimally invasive longitudinal molecular monitoring in diseases where tissue access is inherently limited."

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

Onconic Therapeutics to Present at BIO USA... Expanding Global Partnering for Nesuparib (The Asia Business Daily) - "At the event, CEO John Kim will deliver the company presentation in person on the 24th, introducing the company's key pipeline, research and development capabilities, and global commercialization strategies. The presentation will especially highlight the clinical development achievements and global competitiveness of Nesuparib (JPI-547, Nesuparib), a dual-targeted anticancer drug candidate, emphasizing its potential as a next-generation pan-tumor anticancer therapy."

Clinical • Endometrial Cancer • Gastric Cancer • Ovarian Cancer • Pancreatic Cancer

Safety and efficacy of nesuparib (JPI-547) with gemcitabine-nab-paclitaxel (GemAbraxane) or modified FOLFIRINOX (mFOLFIRINOX) in patients with locally advanced or metastatic PDAC: Results from an ongoing phase Ib/II study. (ASCO 2026) - P1/2 | "Nesuparib combined with GemAbraxane demonstrated acceptable tolerability and encouraging antitumor activity in advanced PDAC. These findings support further evaluation of nesuparib using a 12.5 mg intermittent dosing schedule in the first-line treatment setting; a Phase II trial is currently ongoing."

Clinical • Metastases • P1/2 data • Gastrointestinal Cancer • Neutropenia • Oncology • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Thrombocytopenia

A multicenter, open-label, single-arm, dose-finding and -expansion phase 1b/2 study to evaluate the safety and tolerability of nesuparib (JPI-547) in combination with irinotecan as a third-line and beyond therapy for recurrent or metastatic gastric cancer. (ASCO 2026) - P1/2 | "Approximately 43–49 patients are planned (18–24 in phase 1b; 25 in phase 2). Treatment continues until disease progression, unacceptable toxicity, or study withdrawal."

Clinical • Combination therapy • Metastases • P1/2 data • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor • HRD • UGT1A1