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

Targeting the PLK1-PRMT5 axis enhances radiosensitivity in prostate cancer (AACR 2026) - "Importantly, both PLK1 inhibition (Onvansertib) and PRMT5 inhibition (Onametostat) synergized with ionizing radiation (IR) to suppress tumor growth in vitro and in vivo. These findings highlight a previously unrecognized role of PLK1-mediated PRMT5 phosphorylation in cell cycle control and radiosensitivity, suggesting that targeting the PLK1-PRMT5 axis may serve as a promising therapeutic strategy to enhance radiotherapy efficacy in prostate cancer."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • PLK1 • PRMT5

Comprehensive assay approaches for PRMT5 targeted drug discovery (AACR 2026) - "Here, we established comprehensive assay platforms for PRMT5-targeted drug discovery and validated them using five known inhibitors (LLY-283, JNJ-64619178, GSK591, EPZ015666, and GSK33326595). NanoBRET target engagement intracellular assay results indicated that the PRMT5 inhibitors engaged with the PRMT5/MEP50 complex within one hour of incubation in live HEK293 cells, and Western blot confirmed inhibition of histone H4R3me2s methylation, a key substrate of PRMT5, in MV4-11, Jeko-1, 22RV1, and PC3 cancer cell lines. Collectively, these platforms enable identification, optimization, and mechanistic characterization of PRMT5 inhibitors, accelerating development of selective and potent therapeutic candidates."

Hematological Malignancies • Oncology

CR108485: 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

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

CR108485: A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS (clinicaltrials.gov) - P1 | N=120 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Dec 2021 ➔ Jul 2022

First-in-human • Trial completion date • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

CR108485: A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS (clinicaltrials.gov) - P1 | N=113 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Recruiting ➔ Active, not recruiting | N=190 ➔ 113

Enrollment change • Enrollment closed • First-in-human • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

CR108485: 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

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

CR108485: A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS (clinicaltrials.gov) - P1 | N=138 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial primary completion date: Dec 2021 ➔ Jul 2022

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

CR108485: 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: Jul 2022 ➔ Dec 2022

First-in-human • Trial completion date • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

CR108485: A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS (clinicaltrials.gov) - P1 | N=70 | Recruiting | Sponsor: Janssen Research & Development, LLC | Not yet recruiting ➔ Recruiting

Enrollment open • First-in-human • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

CR108485: A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS (clinicaltrials.gov) - P1 | N=190 | Recruiting | Sponsor: Janssen Research & Development, LLC | N=138 ➔ 190

Enrollment change • First-in-human • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

CR108485: A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS (clinicaltrials.gov) - P1 | N=70 | Not yet recruiting | Sponsor: Janssen Research & Development, LLC

First-in-human • New P1 trial • B Cell Non-Hodgkin Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Solid Tumor

CR108485: A Study of JNJ-64619178, an Inhibitor of PRMT5 in Participants With Advanced Solid Tumors, NHL, and Lower Risk MDS (clinicaltrials.gov) - P1 | N=120 | Recruiting | Sponsor: Janssen Research & Development, LLC | N=70 ➔ 120

Enrollment change • First-in-human • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

CR108485: 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

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

Exploring structural diversity and dynamic stability of small-molecule PRMT5 inhibitors through machine learning-based QSAR and molecular modelling. (PubMed, Mol Divers) - "Analysis of consensus QSAR models identified two highly active PRMT5 inhibitor candidates (CHEMBL4539612 and CHEMBL4577464), with high affinity for binding (- 13.5 to - 13.7 kcal/mol) to the PRMT5 active site and interactions similar to those of the known clinical PRMT5 inhibitor ONAMETOSTAT...Network pharmacology analysis indicated that PRMT5 and its interacting partners are mainly associated with histone arginine methylation and spliceosomal assembly, processes that are frequently dysregulated in MTAP-deficient cancers. These findings suggest CHEMBL4539612 and CHEMBL4577464 as promising scaffolds for the development of selective PRMT5 inhibitors in epigenetic cancer therapy."

Journal • Brain Cancer • Glioblastoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • MTAP

CR108485: 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 | Completed | Sponsor: Janssen Research & Development, LLC | Active, not recruiting ➔ Completed | Trial completion date: Dec 2025 ➔ Sep 2025 | Trial primary completion date: Dec 2025 ➔ Sep 2025

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

Inhibition of PRMT5 with JNJ-64619178 sensitizes B-cell non-Hodgkin lymphoma cells to both intrinsic and extrinsic apoptosis (ASH 2025) - P1 | "Various cell lines, including DLBCL (TMD8, Ri-1, OCI-Ly1,OCI-Ly1R, SUDHL4), double-hit lymphoma patient-derived xenograft (DW19), MCL (Mino, Jeko-1), and BL(Raji, BL-70) were utilized to investigate the in vitro anti-cancer properties of JNJ-9178, BH3 mimetics(venetoclax [Ven, BCL-2i], S63845 [S63, MCL-1i], A1331852 [A133, BCL-xLi]) and TRAIL analogs (rhTRAIL[recombinant human TRAIL], Conatumumab [DR5 agonist], and Mapatumumab [DR4 agonist]). We identified PRMT5 as an important regulator of both intrinsic and extrinsic apoptosis. Ourdata suggest that DBP has the potential to optimize the selection of BH3 mimetics to combine with JNJ-9178 to maximize the activity of this drug across certain B-cell NHL subtypes. Additionally, JNJ-9178sensitizes B-cell NHL cell lines to TRAIL-induced cancer cell-selective extrinsic apoptosis."

IO biomarker • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Solid Tumor • ANXA5 • BCL2 • TNFRSF10B

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

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

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