JZP3508 / Jazz - LARVOL DELTA

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

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

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

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

Reduced severity of radiation esophagitis in mice following 2 weeks of ONC212 treatment [WITHDRAWN] (AACR 2025) - "Radiotherapy administered with curative intent or palliation in lung cancer, esophageal cancer, breast cancer or head and neck cancer is often associated with inflammation, debilitating esophageal injury, pain, difficulty swallowing, and dehydration. 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

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 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

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

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

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

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

Neuroendocrine prostate cancer drivers SOX2 and BRN2 confer differential responses to imipridones ONC201, ONC206, and ONC212 in prostate cancer cell lines. (PubMed, Am J Transl Res) - "The results suggest that treatment of castrate-resistant prostate cancer by imipridones may not be substantially affected by neuroendocrine differentiation as a therapy-resistance mechanism. The results support further testing of imipridones across subtypes of androgen-sensitive and castrate-resistant prostate cancer."

Journal • Preclinical • Brain Cancer • Castration-Resistant Prostate Cancer • CNS Tumor • Endocrine Cancer • Genito-urinary Cancer • Glioma • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor • CLPP • SOX2

TRAIL agonists rescue mice from radiation-induced lung, skin or esophageal injury. (PubMed, J Clin Invest) - "We investigated whether DR5 agonists could rescue mice from toxic effects of radiation and found two different agonists, parenteral PEGylated trimeric-TRAIL (TLY012) and oral TRAIL-Inducing Compound (TIC10/ONC201) could reduce pneumonitis, alveolar-wall thickness, and oxygen desaturation. Irradiated mice had reduced esophagitis characterized by reduced epithelial disruption and muscularis externa thickness following treatment with ONC201 analogue ONC212. The discovery that short-term treatment with TRAIL pathway agonists effectively rescues animals from pneumonitis, dermatitis and esophagitis following high doses of thoracic radiation exposure has important translational implications."

Journal • Preclinical • Breast Cancer • Dermatitis • Dermatology • Fibrosis • Gastrointestinal Disorder • Immunology • Oncology • Pneumonia • Pulmonary Disease • Respiratory Diseases • Solid Tumor • CCL2 • CCL22 • TLR7

Synergistic anti-tumor activity, reduced pERK, and immuno-stimulatory cytokine profiles with 5-FU or ONC212 plus KRAS G12D inhibitor MRTX1133 in CRC and pancreatic cancer cells independent of G12D mutation. (PubMed, Am J Cancer Res) - "We investigated cell viability, drug synergies, pERK suppression and cytokine, chemokine or growth factor alterations following treatment with 5-Fluorouracil (5-FU) or ONC212 plus MRTX1133 in 6 human CRC and 4 human pancreatic cancer cell lines. Our studies reveal preclinical activity of MRTX1133 alone or synergies when combined with 5-FU or ONC212 against mCRC and pancreatic cancer cells regardless of KRAS G12D mutation. The results suggest that KRAS G12V and KRAS G13D should be further considered in clinical trials including combination therapies involving MRTX1133 and 5-FU or ONC212."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CXCL8 • IL18 • KRAS • TNFA

Imipridones inhibit tumor growth and improve survival in an orthotopic liver metastasis mouse model of human uveal melanoma. (PubMed, Br J Cancer) - "Imipridones are a promising strategy for further testing and development in mUM."

Journal • Preclinical • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • CLPP

ONC212, alone or in synergistic conjunction with Navitoclax (ABT-263), promotes cancer cell apoptosis via unconventional mitochondrial-independent caspase-3 activation. (PubMed, Cell Commun Signal) - "Moreover, inhibition of caspase-9 activity unexpectedly augmented, rather than attenuated, caspase-3 activation and the subsequent cell death. Collectively, our research identifies ONC212 as an atypical mitochondrial-independent, yet Bcl-2/Bcl-xL-inhibitable, caspase-3-mediated apoptotic cell death inducer, highlighting its potential for combination therapies in tumors with defective mitochondrial apoptotic signaling."

IO biomarker • Journal • Oncology • ANXA5 • BCL2 • BCL2L1 • CASP3 • CASP8 • CASP9

Neuroendocrine Prostate Cancer Drivers SOX2 and BRN2 Confer Differential Responses to Imipridones ONC201, ONC206, and ONC212 in Prostate Cancer Cell Lines. (PubMed, bioRxiv) - "The results support the idea that treatment of castrate-resistant prostate cancer by imipridones may not be significantly impacted by neuroendocrine differentiation as a therapy-resistance mechanism. The results support further testing of imipridones across subtypes of androgen-sensitive and castrate-resistant prostate cancer."

Journal • Preclinical • Brain Cancer • Castration-Resistant Prostate Cancer • CNS Tumor • Endocrine Cancer • Genito-urinary Cancer • Glioma • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor • CLPP • SOX2

[PREPRINT] Neuroendocrine Prostate Cancer Drivers SOX2 and BRN2 Confer Differential Responses to Imipridones ONC201, ONC206, and ONC212 in Prostate Cancer Cell Lines (bioRxiv) - "Slight protection from ONC201 or ONC206 with SOX2 and BRN2 overexpression was observed in the inducible LNCaP cells but not in the DU145 cells. At 2 months, there was an apparent increase in CLpP expression in LNCaP SOX2-overexpressing cells but this did not confer enhanced sensitivity to ONC201. DU145 SOX2-overexpressing cells had a significantly reduced ONC201 sensitivity than DU145 control cells. The results support the idea that treatment of castrate-resistant prostate cancer by imipridones may not be significantly impacted by neuroendocrine differentiation as a therapy-resistance mechanism."

Preclinical • Preprint • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor