onametostat (JNJ-64619178) / J&J - LARVOL DELTA

Potential novel interventions of oncohistones, epigenetic modifications, and RNA processing machinery in betel-nuts related HNSCC in Taiwan (AACR 2025) - "PI3K/AKT/mTOR interventions, ALK/IGF1R inhibitor, CDK4/6 inhibitor, BCl2 inhibitor, WEE1 inhibitor, ATR inhibitor, DNA-PK inhibitor, AT2AR inhibitor, Mcl-1 inhibitor, MEK1/2 inhibitor, JAK2 inhibitor, CXCR4 inhibitor, FAK inhibitor, p53 reactivator, MDM2 inhibitor, SHP2 inhibitor, PARP7 inhibitor, IAP inhibitor, GLS1 inhibitor, eribulin, & VEGFR2/ PDGFR/FGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse treatment refractoriness, through the inhibition of mesenchymal transformation, pRB, & PI3K/AKT /mTOR signaling and modulation of stemness & PD1/PDL1 pathway...Disrupting NSD1 in HNSCC cell lines led to CpG hypomethylation & enhanced cisplatin sensitivity. TW2.6 used to test (1)in vitro drug sensitivity to (a)Chemical Modulators of Splicing; (b)PRMT5 inhibitor; (c)CDK9 inhibitor, EZH2i, DNMT3i, BRD/BET4i, and HDACi; (d)NSD1/SETD2 inhibitor; (e)METTL3 inhibitor; (2)synergistic effects with other therapies by MTT assay, colony..."

IO biomarker • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma of Head and Neck • AKT1 • ALK • ARID1B • ATM • AXL • BRD4 • CCND3 • CDK12 • CXCR4 • DDR2 • EPHB1 • FAT1 • FGF10 • FGFR • FLCN • HRAS • KDM5A • KDR • METTL3 • MITF • NSD1 • PDGFRB • PIK3CA • RICTOR • RPS6KB1 • SDHA • SETD2 • SOX9 • STK11 • TERT • TIPARP • TMB • TNFAIP3

PRMT5 as a target in CRC interception: Synthetic lethal dependency identified in APC-LOF preclinical models of FAP disease (AACR 2025) - "JNJ-64619178 (JNJ-9178), a potent clinical PRMT5 inhibitor, demonstrated an >800-fold window in growth inhibition of engineered APCKO organoids compared to wild-type (WT). To address these dose-limiting toxicities, we have developed a GI-restricted approach and discovered new compounds that only inhibit PRMT5 activity locally in the intestinal tract. This strategy is detailed in a second abstract."

Preclinical • Synthetic lethality • Colorectal Cancer • Oncology • Solid Tumor • APC

A Rollover Study for Continued Study Treatment and Ongoing Safety Monitoring (clinicaltrials.gov) - P1 | N=80 | Enrolling by invitation | Sponsor: Janssen Research & Development, LLC

New P1 trial • Acute Myelogenous Leukemia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Castration-Resistant Prostate Cancer • Chronic Lymphocytic Leukemia • Genito-urinary Cancer • Hematological Malignancies • Leukemia • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer • Solid Tumor

Synergistic Efficacy of Dual Menin and PRMT5 Targeting Against NPM1 mutated and KMT2A-rearranged Leukemia (ASH 2024) - "First, we assessed the PRMT5-i JNJ-64619178 (JNJ) and GSK3326595 (GSK) as single drugs...There was significant drug synergy of both PRMT5-i with each of two novel Men-i VTP50469 (VTP) and KO-539, while we found only moderate growth inhibition and no synergy in HL60 cells (wildtype for KMT2A and NPM1) that served as negative control...Four weeks of in vivo treatment significantly reduced leukemia burden in peripheral blood and bone marrow and significantly enhanced mice survival compared to single drugs and vehicle control. The presented data underscore the therapeutic potential of combined Menin and PRMT5 inhibition as a novel synergistic approach to targeting NPM1mut and KMT2A-r leukemias and is already available for clinical investigation."

Clinical • Hematological Malignancies • Leukemia • Oncology • ANXA5 • ITGAM • JAK2 • KMT2A • MEIS1 • MEN1 • NPM1 • PBX3 • PRMT5

A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS (clinicaltrials.gov) - P1 | N=114 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Metastases • Trial completion date • Trial primary completion date • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

One stone two birds: Introducing piperazine into a series of nucleoside derivatives as potent and selective PRMT5 inhibitors. (PubMed, Eur J Med Chem) - "Moreover, compound 36 had more favorable metabolic stability and aqueous solubility than JNJ64619178 (9). Meanwhile, it obviously suppressed the tumor growth in a MOLM-13 tumor xenograft model. These results clearly indicate that 36 is a highly potent and selective PRMT5 inhibitor worthy for further development."

Journal • Oncology

Loss-of-function and gain-of-function genetic screens identify potential biomarkers and combination partners for the highly selective allosteric PI3Kδ inhibitor roginolisib (IOA-244) (EORTC-NCI-AACR 2024) - "Since the latter group contains possible therapeutic targets, we combined roginolisib with the KDM5A inhibitor GSK467 and with PRMT5 inhibitor onametostat in three MCL cell lines (Z138, SP53, SP49), observing synergism/additivity in 3/3 and 2/3 models, respectively. Conclusions. A genome-wide genetic screening identified genes modulating the lymphoma cells' response to the roginolisib, identifying potential biomarkers of response and providing combination partners to be further explored."

Biomarker • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • ARID1A • ARID1B • CCNE1 • CDKN1A • CDKN1C • CHD8 • CREBBP • EP300 • FLI1 • KDM5A • LYN • NFKBIA • NFKBIE • PIK3CD • PLK1 • PTEN • SMARCA4 • SMARCA5 • TNFRSF10A • TOX4 • TP73

Onametostat, a PfPRMT5 inhibitor, exhibits antimalarial activity to Plasmodium falciparum. (PubMed, Antimicrob Agents Chemother) - "Consistent with the function of PfPRMT5 in mediating symmetric dimethylation of histone H3R2 (H3R2me2s) and in regulating invasion-related genes, onametostat treatment led to the reduction of H3R2me2s level in P. falciparum and caused the defects on the parasite's invasion of red blood cells. This study provides a starting point for identifying specific PRMT inhibitors with the potential to serve as novel antimalarial drugs."

Journal • Infectious Disease • Malaria

Combination of MTA-cooperative PRMT5 inhibitor and direct mutant-selective KRAS inhibitors as a novel therapeutic approach for MTAP-deficient pancreatic cancer (AACR 2024) - "We found that suppression of PRMT5 activity using two distinct first-generation clinical candidate small molecule inhibitors (JNJ-64619178 and GSK3326595) demonstrated single agent activity and reduced PDAC cell growth...In support of our hypothesis, we demonstrated that combination treatment with MRTX1719 and mutant selective KRAS inhibitors (G12Ci/MRTX849 and G12Di/MRTX1133) further sensitized KRASG12C/D-mutant PDAC cells to KRAS inhibition in short- and long-term growth assays as well as in vivo xenograft studies. Our ongoing studies are evaluating the consequences of co-targeting PRMT5 and KRAS on gene expression changes using RNA-Seq and cancer cell signaling pathways using RPPA analyses. In summary, our data support concurrent inhibition of PRMT5 and KRAS as a promising therapeutic strategy for MTAP-deficient KRAS-mutant pancreatic cancer."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • MTAP

Inhibition of epigenetic and cell cycle-related targets in glioblastoma cell lines reveals that onametostat reduces proliferation and viability in both normoxic and hypoxic conditions. (PubMed, Sci Rep) - "In U-251 MG and U-87 MG cells, onametostat also affected the spheroid formation at concentrations lower than the currently used chemotherapeutic drug lomustine. Further validation by immunostaining in three cell lines confirmed that onametostat affects cell cycle and causes reduction in nucleolar protein levels. In this way, inhibition of epigenetic targets might represent a viable strategy for glioblastoma treatment even in the case of decreased chemo- and radiation sensitivity, although further studies in clinically more relevant models are required."

Journal • Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

MYCN and SNRPD3 cooperate to maintain a balance of alternative splicing events that drives neuroblastoma progression. (PubMed, Oncogene) - "Indeed, the PRMT5 inhibitor, JNJ-64619178, reduced cell viability and SNRPD3 methylation in neuroblastoma cells with high SNRPD3 and MYCN expression...Third, this leads to balanced alterative splicing (AS) activitiy that is favorable to neuroblastoma. Together this forms as a therapeutic vulnerability where SNRPD3 perturbation or PRMT5 inhibitors are selectively toxic to neuroblastoma by conditionally disturbing splicing activity."

Journal • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • BIRC5 • MYCN • SNRPD3

Phase 1 study of JNJ-64619178, a protein arginine methyltransferase 5 inhibitor, in patients with lower-risk myelodysplastic syndromes. (PubMed, Leuk Res) - "A tolerable dose of JNJ-64619178 was identified in patients with LR MDS. However, no evidence of clinical benefit was observed."

Clinical • Journal • P1 data • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Neutropenia • Oncology • Thrombocytopenia • SF3B1

A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS (clinicaltrials.gov) - P1 | N=114 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Dec 2023 ➔ Dec 2024 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Metastases • Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Advanced Solid Tumors (Clin Cancer Res) - P1 | N=114 | NCT03573310 | Sponsor: Janssen Research & Development, LLC | "Adult patients with treatment-refractory advanced solid tumors or non-Hodgkin lymphomas and measurable disease received escalating doses of JNJ-64619178....Ninety patients received JNJ-64619178. Thrombocytopenia was identified as the only dose-limiting toxicity. JNJ-64619178 showed dose-proportional PK and robust target engagement, as measured by plasma symmetric dimethylarginine, across all dose levels. The objective response rate was 5.6% (5 of 90). Patients with adenoid cystic carcinoma (ACC) had an ORR of 11.5% (3 of 26) and a median progression-free survival of 19.1 months."

P1 data • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Advanced Solid Tumors. (PubMed, Clin Cancer Res) - "JNJ-64619178 demonstrated manageable dose-dependent toxicity and preliminary evidence of antitumor activity in ACC and other tumor types. Plasma exposure was dose dependent, and target inhibition was maintained with intermittent and continuous dosing. Based on safety, clinical activity, PK, and PD findings, two provisional RP2Ds were selected: 1.5 mg intermittently and 1.0 mg once daily. Aside from ACC, clinical benefit was limited, and biomarkers to enrich for responsiveness to PRMT5 inhibition will be needed for further development."

Clinical • Journal • Metastases • P1 data • Adenoid Cystic Carcinoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Thrombocytopenia • PRMT5

PH020-803: an MTA-cooperative and brain-penetrable PRMT5 inhibitor that selectively targets MTAP-deleted tumors (AACR 2023) - "Based on the synthetic lethality interaction, an MTA cooperative PRMT5 inhibitor has the potential to selectively target MTAP-deleted tumors and avoid hematologic toxicity of substrate-competitive (such as GSK3326595) or SAM-competitive (such as JNJ64619178) PRMT5 inhibitors. A pair of HCT116 isogenic cell lines (MTAP-/- and MTAP+/+) were used to determine the effects of PH020-803 on cell proliferation and intracellular symmetric dimethylarginine (SDMA) content. The present data suggest that PH020-803 is an MTA-cooperative and brain-penetrable PRMT5 inhibitor that selectively targets MTAP-deleted tumors."

Brain Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • ABCB1 • CD34 • MTAP • PRMT5

Combination therapeutic strategy with type I PRMT inhibition in cancer treatment (AACR 2023) - "We validated the synergistic effects and mechanisms of combined treatment with a type I PRMT inhibitor and a PRMT5 inhibitor (JNJ-64619178, GSK3326595/EPZ015938 or an in-house PRMT5i) using cell-based assays and in vivo studies...In vitro and in vivo studies revealed that inhibitors of type I PRMT and MAT2A (AG-270) dosing combination indeed exhibited stronger anti-cancer activity than mono-treatment...In vivo, the combination of type I PRMT inhibitor with different FLT3 inhibitors (Gilteritinib, Midostaurin, or CTS2016) led to deeper antitumor responses in a variety of FLT3-ITD AML models. Taken together, these findings support the co-administration of type I PRMT inhibitor with various therapies including epigenetic reprogramming, cancer metabolism modulation, or targeted therapies for receptor tyrosine kinases, which could benefit cancer patients as a promising therapeutic strategy."

Combination therapy • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • FLT3 • MAT2A • PRMT1 • PRMT5

JNJ-64619178 radiosensitizes and suppresses fractionated ionizing radiation-induced neuroendocrine differentiation (NED) in prostate cancer. (PubMed, Front Oncol) - "It targets NED induced by FIR in prostate cancer cells. JNJ-64619178 can radiosensitize and suppress NED induced by FIR in prostate cancer cells and can be a potential radiosensitizer for prostate cancer treatment."

Journal • Brain Cancer • CNS Tumor • Genito-urinary Cancer • Glioblastoma • Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • PRMT5

Inhibition of PRMT5 Increases Sensitivity to BH3 Mimetics in Aggressive B Cell Malignancies (ASH 2022) - P1 | "The DLBCL cell lines (HBL1, TMD8, RI-1, OCI-Ly1, Karpas 422, SUDHL4, Toledo), double hit lymphoma (DHL) patient-derived xenograft (PDX) cell lines (DW19), mantle cell lymphoma (MCL) cell lines (Mino, Jeko-1), T cell acute leukemia (T-ALL) cell line (Jurkat) and Burkitt lymphoma (BL) cell line (Raji) were used to investigate the in vitro anti-cancer activity of JNJ-64619178 (Janssen Pharmaceuticals) and BH3 mimetics (venetoclax [BCL2i], S63845 [MCL-1i] and A1331852 [BCL-xLi], Selleckchem). The combination of a PRMT5 inhibitor with BH3 mimetics, especially venetoclax, is worthy of further exploration as a potential therapeutic strategy for DLBCL and MCL."

Burkitt Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • T Acute Lymphoblastic Leukemia • ANXA5 • PRMT5

JNJ-64619178 radiosensitizes and suppresses fractionated ionizing radiation-induced neuroendocrine differentiation (NED) in prostate cancer (Front Oncol) - "JNJ-64619178 inhibits DNA damage repair in prostate cancer cells independent of their AR status. JNJ-64619178 impairs the repair of ionizing radiation-induced damaged DNA by transcriptionally inhibiting the DNA damage repair gene expression and radiosensitizes prostate, glioblastoma and lung cancer cell line. It targets NED induced by FIR in prostate cancer cells."

Preclinical • Brain Cancer • CNS Tumor • Genito-urinary Cancer • Glioblastoma • Glioma • Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • Thoracic Cancer

Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Patients with Lower-Risk Myelodysplastic Syndromes (ASH 2021) - "Pts had a median of 1 prior line of therapy post-ESA (range 0-4), including lenalidomide (33%), hypomethylating agents (29%), and luspatercept (19%). Despite robust target engagement, clinical activity was not observed, and enrollment was stopped. The role of PRMT5 in MDS and the differential impact of PRMT5 inhibition on normal and malignant hematopoiesis require further study."

Clinical • P1 data • Acute Myelogenous Leukemia • Anemia • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Heart Failure • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Myelodysplastic Syndrome • Neutropenia • Oncology • Solid Tumor • Thrombocytopenia • PRMT5 • SF3B1 • TNNI3

"Select projects targeting synthetic lethality TNG908 MRTX1719 SKL27969 AMG 193 AG-270 IDE397 JNJ-64619178 PRT543 PRT811 RP-6306 GSK3326595 GSK3368715 PF-06939999 JBI-778 TNG462 ISM020 AGX323 AT101/ AT201 @JacobPlieth @evaluatepharma https://t.co/74gBPzNLcn https://t.co/5Um0uV9GAB" (@BRAINCURES)

Synthetic lethality

Protein arginine methyltransferase 5 is essential for oncogene product EWSR1-ATF1-mediated gene transcription in clear cell sarcoma. (PubMed, J Biol Chem) - "Furthermore, we demonstrate that the clinical-stage PRMT5 inhibitor JNJ-64619178 potently and efficaciously inhibited CCSST cell growth in vitro and in vivo. These results provide new insights into PRMT5 as a transcription regulator and warrant JNJ-64619178 for further clinical development to treat CCSST patients."

Journal • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • ATF1 • EWSR1 • PRMT5

Protein Arginine Methyltransferase 5 (PRMT5) Inhibitors in Oncology Clinical Trials: A review. (PubMed, J Immunother Precis Oncol) - "Partial response has been seen in adenoid cystic carcinoma from both GSK3326595 and JNJ-64619178, with four cases of stable disease seen with PRT543. Highly significant is a durable complete response in isocitrate dehydrogenase 1-mutated glioblastoma multiforme with PRT811...Further studies are warranted, and there are clinical trials to come whose data will be telling of the efficacy of PRMT5 inhibitors in both hematologic and solid malignancies. The aim of this study is to compile available results of PRMT5 inhibitors in oncology clinical trials."

IO biomarker • Journal • Review • Adenoid Cystic Carcinoma • Brain Cancer • Glioblastoma • Hematological Disorders • Oncology • Solid Tumor • IDH1 • PRMT5

A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS (clinicaltrials.gov) - P1 | N=114 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Dec 2022 ➔ Dec 2023 | Trial primary completion date: Jul 2022 ➔ Dec 2023

Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor