We demonstrate that GSK3368715, a small-molecule inhibitor of PRMT1, downregulates the protein levels of the histone lysine methyltransferase SUV39H1 by enhancing its ubiquitination...Importantly, the combination of dual inhibition with anti-PD-L1 antibody enhances the responsiveness of breast cancer to immunotherapy. Taken together, our findings indicate that co-targeting PRMT1 and SUV39H1 represents a promising therapeutic strategy for breast cancer.

We show that PTK6 is targeted by PRMT1 and mutation of PTK6 R131/R136 or R132, or treatment with the type 1 PRMT inhibitor GSK3368715, leads to decreased arginine methylation, increased PTK6 protein stability and impaired PTK6 association with its substrates...These results indicate that arginine methylation is a key regulatory switch for PTK6 signaling and protein turnover and may be central for the execution of its diverse context-specific functions. Mutation of PTK6 arginine residues has been reported in some cancers, which may contribute to disease-specific PTK6 expression and signaling.

Treatment with the Type I PRMT inhibitor GSK3368715 resulted in a dose-dependent reduction in cell survival across a panel of MM cell lines...This was supported by Reverse Phase Protein Array (RPPA) analyses, which revealed a significant reduction in levels of proteins associated with cell cycle regulation and DDR pathways. Overall, our findings indicate that MM cells critically depend on PRMT1 for survival, highlighting the therapeutic potential of PRMT1 inhibition in treating MM.

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.

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. .

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.

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.

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.

Treatment with the Type I PRMT inhibitor GSK3368715 resulted in a dose-dependent reduction in cell survival across a panel of MM cell lines...This was supported by Reverse Phase Protein Array (RPPA) analyses, which revealed a significant reduction in levels of proteins associated with cell cycle regulation and DDR pathways. Overall, our findings indicate that MM cells critically depend on PRMT1 for survival, highlighting the therapeutic potential of PRMT1 inhibition in treating MM.

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.

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.

Mechanistically, PRMT1 was shown to promote M2 macrophage polarization, thereby contributing to CoNV, through the FGF2/PI3K/Akt pathway. Therefore, targeting PRMT1 may offer a promising therapeutic approach.