MS023 / University of Montreal, McGill University - LARVOL DELTA

Developing epigenetic synergistic drug combinations with albendazole in paediatric acute myeloid leukaemia (ASH 2025) - "Similar anthelmintic agents, mebendazole (MBZ) and parbendazole (PBZ), have been reported to have effects on epigenetic regulators that alter C-MYB degradation (Walf-Vorderwülbecke et al...These epigenetic hits represent various target families such as HDAC inhibitors (vorinostat, panobinostat, and CUDC-101), BET inhibitors (OTX-015, PFI-1, and (-)-JQ), aurora kinase inhibitors (MK-8745 and JNJ-7706621), and DNA synthesis inhibitors (cytarabine)...HDAC inhibitors (vorinostat), BET inhibitors (OTX-015) and histone methyltransferase (MS023) were among the most represented epigenetic target families, indicating potential mechanism of action of the novel ABZ+epigenetic combination. The novel drug candidate ABZ was found to have remarkable anti-leukaemia efficacy in murine and human models of childhood AML in vitro and in vivo while having negligible effects in normal cells. Current work is focused on evaluating ABZ+epigenetic synergistic combinations that will be taken..."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Pediatrics • HOXA9 • IL1B • MEIS1

Targeting type I PRMTs in ALS: in vivo evaluation of MS023 and GSK3368715 in TDP43Q331K and SOD1G93A mice (ALS-MND 2025) - "Higher CNS exposures of MS023 and GSK3368715, were achieved using elacridar (50 mg/kg, PO), a P-glycoprotein inhibitor, which was therefore used in all subsequent studies. Both compounds were well-tolerated up to 50 mg/kg, with higher doses causing weight loss. In TDP43Q331K mice, plasma ADMA levels were elevated relative to wild-type controls and were reduced by GSK3368715, but not by MS023."

Preclinical • Plasma NfL • TARDBP

Hypoxia-Induced PRMT1 Lactylation Drives Vimentin Arginine Asymmetric Dimethylation in Tumor Metastasis. (PubMed, Adv Sci (Weinh)) - "PRMT1 inhibitor MS023 reduces xenograft metastasis with low toxicity. These findings establish a hypoxia-PRMT1-vimentin axis, identifying vimentin R64 aDMA as a metastatic regulator. Inhibiting PRMT1 represents a promising anti-metastasis strategy."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HDAC8 • PRMT1 • VIM

PRMT1-mediated metabolic reprogramming promotes leukemogenesis. (PubMed, Elife) - "The PRMT1 inhibitor, MS023, effectively cured this PRMT1-driven leukemia...Furthermore, administering the glucose analog 2-deoxy-D-glucose delayed AMKL progression and promoted cell differentiation. Ectopic expression of Cpt1a rescued the proliferation of 6133 cells ectopically expressing PRMT1 in the glucose-minus medium. In conclusion, PRMT1 upregulates glycolysis and downregulates fatty acid oxidation to enhance the proliferation capability of AMKL cells. ."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • CPT1A • PRMT1 • RBM15

Epidrug screening identifies type I PRMT inhibitors as modulators of lysosomal exocytosis and drug sensitivity in cancers. (PubMed, Cell Death Dis) - "Two type I PRMT inhibitors, MS023 and GSK3368715, showed synergy with cisplatin, reduced cell viability, and inhibited lysosomal exocytosis without altering lysosomal biogenesis gene expression. These inhibitors also synergized with other lysosome-sequestered drugs, indicating a broader application in overcoming drug resistance. Analysis of patient data further linked lower type I PRMT levels to better responses, highlighting their potential as combination therapy candidates to enhance chemotherapy efficacy and improve cancer survival rates."

Journal • Oncology

THERAPEUTIC STRATEGIES TARGETING SRSF2 AND KIT MUTATIONS IN SYSTEMIC MASTOCYTOSIS (EHA 2025) - "The efficacy of KIT TKIs midostaurin and avapritinib, and the synergistic effects of spliceosome inhibitors MS023, RKI-1447, and CTX-712 were also evaluated. Our findings suggest that combining KIT TKIs with spliceosome inhibitors represents a promising therapeutic approach for SM. The study highlights the role of SRSF2 and KIT mutations in driving MC malignancy and emphasizes the potential of targeting the spliceosome machinery to overcome drug resistance, potentially improving treatment outcomes for advanced SM."

Oncology • KIT • SRSF2 • STAT5

Arginine methylation by protein arginine methyltransferase 1 (PRMT1) affects ADAMTS13 activity (ISTH 2025) - "Results We show that an inhibition of arginine methylation by a PRMTs inhibitor (MS023) in HEK293 cells expressing rADAMTS13 (Fig...Site-directed mutagenesis replacing 5 highly conserved methylation sites (R193, R498, R692, R1123, and R1206) led to identification of the critical role of R1206 in rADAMTS13 function. R1206K variant exhibited a 4~5 fold increased activity, likely resulting from conformational changes that abolished alloteric autoinhibition of ADAMTS13 function. Table or Figure Upload"

Cardiovascular • Hematological Disorders • Infectious Disease • Inflammation • Ischemic stroke • Mood Disorders • Novel Coronavirus Disease • Thrombocytopenic Purpura • PRMT1

Methylation of RBM39 by PRMT6 enhances resistance to Indisulam in non-small cell lung cancer by promoting alternative splicing of proto-oncogenes. (PubMed, PLoS Biol) - "Inhibiting PRMT6 with MS023 or mutating the RBM39 methylation site enhances Indisulam sensitivity in NSCLC and significantly improves its anti-tumor efficacy. Our findings identify methylated RBM39 as a key biomarker of Indisulam resistance and suggest a potential therapeutic strategy for NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • PRMT6 • RBM39

PRMT1 inhibitor MS023 suppresses RNA splicing to sensitize small cell lung cancer to DNA damaging agents. (PubMed, Neoplasia) - "Among these, MS023, a PRMT inhibitor, showed the greatest synergy with cisplatin and etoposide across various SCLC cell lines. Additionally, MS023 enhanced the effects of IR and the PARP inhibitor talazoparib, both in vitro and in vivo. Therefore, targeting PRMT1 in combination with DNA-damaging therapies presents a promising strategy to improve treatment outcomes for SCLC."

Journal • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • PRMT1

Prmt1-mediated methylation regulates Ncoa4 stability to transactivate Adamts genes and promote bone extracellular matrix degradation in chronic hematogenous osteomyelitis. (PubMed, Biol Direct) - "These findings identify Prmt1 as a pivotal regulator of bone ECM degradation in osteomyelitis through stabilization of Ncoa4 and highlight Prmt1 as a promising therapeutic target for osteomyelitis treatment."

Journal • Inflammation • Targeted Protein Degradation • ADAMTS3 • CREBBP • NCOA4 • PRMT1 • RNF8

Inhibitors of the enzyme Arginine Methyltransferase (PRMT) are identified as radiosensitizers in glioblastoma cells through a chemical screen (ESTRO 2025) - "PRMT inhibitors (MS023, MS049, SGC707, and LLY283) were tested on U373 and U87 GBM cell lines, and the optimal drug doses were determined through cell viability and colony formation assays. These findings establish a foundational framework for identifying RT resistance mechanisms and devising innovative combination therapy strategies tailored for GBM. The observed effects of PRMT inhibition on RT response offer promising avenues for future research and potential clinical applications."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • PRMT1

Discovery of a first-in-class protein arginine methyltransferase 1 (PRMT1) degrader for nonenzymatic functions studies. (PubMed, Eur J Med Chem) - "Among them, only GSK3368715 advanced to clinical trials but was discontinued in phase I due to inadequate efficacy and thrombosis toxicity. Notably, as anticipated, CM112 could target PRMT1's nonenzymatic function by downregulating the stability of the orphan receptor TR3, an effect not observed with the PRMT1 inhibitor MS023, that is in consistence with the previous findings. Taken together, CM112 represents a valuable tool for elucidating the unknown, methyltransferase-independent roles of PRMT1 in disease progression and pave the way for developing more potent and drug like PRMT1 degraders in future."

Journal • Cardiovascular • Hematological Disorders • Oncology • Solid Tumor • Thrombosis • PRMT1 • PRMT3

Opto-Epigenetic Regulation of Histone Arginine Asymmetric Dimethylation via Type I Protein Arginine Methyltransferase Inhibition. (PubMed, J Med Chem) - "Importantly, visible light irradiation at 420 nm could trigger the photolysis of the prodrug, thereby liberating MS023 for effective downregulation of histone arginine asymmetric dimethylation and DNA replication-related transcriptomic activities. This opto-epigenetic small-molecule prodrug potentially aids in further research into the pathophysiological functions of type I PRMTs and the development of targeted epigenetic therapeutics."

Journal • Gene Therapies • Infectious Disease • Oncology

Arginine Methylation by PRMT1 Affects ADAMTS13 Secretion and Enzymatic Activity. (PubMed, Arterioscler Thromb Vasc Biol) - "An inhibition of arginine methylation by a PRMT inhibitor (a type I methyl transferase inhibitor, MS023) in human embryonic kidney 293 cells expressing recombinant ADAMTS13 and mice results in a significant reduction of ADAMTS13 secretion, but the secreted ADAMTS13 shows an increased specific activity; conversely, overexpression of PRMT1 in human embryonic kidney 293 cells and mice results in an increase of ADAMTS13 secretion, but the secreted ADAMTS13 exhibits a significantly reduced proteolytic activity...Site-directed mutagenesis of 5 highly conserved methylation sites (R193, R498, R692, R1123, and R1206) identifies the critical role of R1206 in ADAMTS13 function...These results demonstrate the crucial role of arginine methylation on ADAMTS13 secretion and activity. Our findings may shed new light on the mechanism of allosteric regulation of ADAMTS13, which may have a therapeutic implication."

Journal • Cardiovascular • Hematological Disorders • Thrombocytopenic Purpura • Thrombosis • PRMT1

PRMT1 Promotes the Self-renewal of Leukemia Stem Cells by Regulating Protein Synthesis. (PubMed, Adv Sci (Weinh)) - "Pharmacological inhibition of PRMT1 activity by MS023 remarkably eliminates LSCs and prolongs the survival of CML mice...PRMT1 augments the global protein synthesis via RPL29 in CML LSCs. Taken together, the findings provide new evidence that histone arginine methylation modification regulates protein synthesis in LSCs and highlight PRMT1 as a valuable druggable target for patients with CML."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • BCR • PRMT1

Analysis of TDP-43 splicing targets in cytoplasmic and nuclear fractions from C9orf72 iPSC-derived motor neurons (ALS-MND 2024) - "We show the presence of C9-HRE is associated with significant changes to several TDP-43 splicing targets in both cytoplasmic and nuclear RNA fractions, and that MS023 reduces STMN2-CE and UNC13A-CE abundance, suggesting potential therapeutic relevance. Ongoing analysis of control and C9orf72-KO MNs treated with polyGR(15) and MS023 will help determine the mechanism by which type-I PRMT inhibition rescues DPR challenge effects. Analysis of RNA-Seq results will help validate qPCR data and identify additional gene expression and splice alterations in the context of C9orf72 iPSC-MNs and PRMT inhibition."

HDGF • STMN2 • TARDBP

Development of a dipeptide repeat protein (DPR) challenge assay in larval zebrafish for screening protective compounds (ALS-MND 2024) - "Preliminary results suggest that the PRMT inhibitor MS023 may have a protective effect when administered before PR15... PR15 dose-dependently reduces survival in 4dpf wild-type zebrafish. Doses of 1ug/mL, 1.5ug/mL, 2ug/mL, and 2.5ug/mL show increasing toxicity, with doses above 3ug/mL causing complete lethality after 24 hours, and doses below 1ug/mL rarely affecting survival. At 2ug/mL, PR15 reduces mean group survival by approximately 75% compared to untreated and vehicle controls (p < 0.0001)."

PRMT1 inhibition perturbs RNA metabolism and induces DNA damage in clear cell renal cell carcinoma. (PubMed, Nat Commun) - "PRMT1-specific proteomics reveals an interactome rich in RNA binding proteins and further investigation indicates significant widespread disruptions in mRNA metabolism with both MS023 treatment and PRMT1 knockdown, resulting in R-loop accumulation and DNA damage over time. Our data supports PRMT1 as a target in ccRCC and informs a mechanism-based strategy for translational development."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • PRMT1 • VHL

Dysregulated DNA repaired elicited by type 1 PRMT inhibitor in clear cell renal cell carcinoma enables development of novel combination therapies (AACR 2024) - "Additionally, mitomycin C (MMC) is a clinically approved compound that induces ICLs. Our current knowledge base indicates that MS023 holds promise for clinical investigation, both as a standalone treatment and in combination with Talazoparib or MMC. These results present an exciting opportunity to shed new light on the challenging therapeutic landscape faced by ccRCC patients today."

Combination therapy • Breast Cancer • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • BRCA

PRMT1 is a critical dependency in clear cell renal cell carcinoma with roles in post- transcriptional regulation and DNA damage response (AACR 2024) - "Among the several promising targets identified, a particularly favorable inhibition profile was noted for MS023, an inhibitor of the type I protein arginine methyltransferase family (PRMT1/3/4/6 and 8)...This growth inhibition was corroborated using an additional type I PRMT compound, GSK3368715...Our data suggests that inhibition of PRMT1 inhibits processing of mRNA transcripts, compromises DDR mechanisms, leading to an accumulation of double stranded breaks, cytostasis and cell death. Thus PRMT1 represents a viable therapeutic target in ccRCC."

Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • BAP1 • PBRM1 • PRMT1 • SETD2 • VHL

The antidepressant effects of protein arginine methyltransferase 2 involve neuroinflammation. (PubMed, Neurochem Int) - "Furthermore, the PRMT2 inhibitor MS023 was administered to the animals to investigate whether the antidepressant effect of PRMT2 overexpression could be reversed...In summary, PRMT2 overexpression in the hippocampus promoted the conversion of microglia from the M1 to M2 type, resulting in an antidepressant effect. These results suggest that PRMT2 may be a potential therapeutic target to prevent and treat depression."

Journal • CNS Disorders • Depression • Inflammation • Psychiatry • ARG1 • PRMT2

Enhancement of PRMT6 binding to a novel germline GATA1 mutation associated with congenital anemia. (PubMed, Haematologica) - "Moreover, treatment of the PRMT6 inhibitor MS023 could partially rescue the inhibited transcriptional and impaired erythroid differentiation caused by the GATA1 mutation. Taken together, our results provide molecular insights into erythropoiesis in which mutation leads to partial loss of GATA1 function and the broader role of PRMT6 and its inhibitor MS023 in congenital anemia, highlighting PRMT6 binding as a negative factor of GATA1 transcriptional activity in aberrant hematopoiesis."

Journal • Anemia • Hematological Disorders • Thrombocytopenia • GATA1

Type-I protein arginine methyltransferase inhibition primes anti-programmed cell death protein 1 immunotherapy in triple-negative breast cancer. (PubMed, Cancer) - "Targeting type-I PRMT can potentially improve immunotherapeutic efficacies in patients with TNBC. By enhancing the tumor immunogenicity and promoting a more favorable immune microenvironment, this combined approach may enable more patients with TNBC to benefit from immunotherapies."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8

PRMT inhibitor promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue SMA mice. (PubMed, EMBO Mol Med) - "Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. Moreover, transcriptomic analysis revealed that MS023 treatment has minimal off-target effects, and the added benefit is mainly due to targeting neuroinflammation. Our study warrants further clinical investigation of PRMT inhibition both as a stand-alone and add-on therapy for SMA."

Journal • Preclinical • Genetic Disorders • Inflammation • Movement Disorders • Muscular Atrophy • Rare Diseases

Protein arginine methyltransferase 1 is a therapeutic vulnerability in multiple myeloma. (PubMed, Front Immunol) - "The elevated expression of PRMT1 in relapsed/refractory patients underscores its potential as a target for overcoming treatment resistance. Moreover, our results highlight the efficacy of MS023 as a promising therapeutic agent against MM, offering new avenues for therapeutic approaches in relapsed/refractory MM."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • PRMT1