PRMT5 overexpression

Additionally, by filtering PRMT5-correlated genes within the HIF1α pathway and selecting up/downregulated genes in HCC patients, we identified Ras-related nuclear protein (RAN) as a target associated with overall survival. For the first time, we report that PRMT5 is implicated in the regulation of HIF1A and RAN genes, suggesting the potential prognostic utility of PRMT5 in HCC.

Furthermore, this study demonstrated that the PRMT5 inhibitor C9 significantly enhanced the sensitivity of lung cancer cells to carboplatin. These findings suggest that targeting PRMT5-mediated autophagy with C9 can overcome hypoxia-induced carboplatin resistance and improve the efficacy of chemotherapy in patients with cancer.

Lastly, we report the development of a SAM-competitive PRMT5 inhibitor, PRT382, with exclusive selectivity and optimal in vitro and in vivo activity compared to available PRMT5 inhibitors. Taken together, the discovery that PRMT5 drives oncogenic pathways promoting RT provides a compelling rationale for clinical investigation of PRMT5 inhibitors such as PRT382 in aggressive CLL/RT cases.

Our data indicates that PRMT5 promoted colorectal cancer proliferation partially through activating glycolysis and may be a potential target for colorectal cancer therapy.

Further silencing of VEGFA in RB cells overexpressing PRMT5 constrained the expression of MMP1, MMP2 and MMP9, and suppressed the growth of tumors in mice. In conclusion, this study clarifies that the depletion of PRMT5 reduces H3K4me3-mediated VEGFA transcription and retards the carcinogenesis of RB by suppressing the expression of MMPs.

Tg813 engrafted animals treated with C220 (10mg/kg) showed improved survival compared to vehicle-treated mice (p<0.001). This preclinical model supports the hypothesis that PRMT5 over-expression provides cancer driver activity and a unique opportunity to study the role of this oncogene in an immune-competent, in vivo model system.

CircPRMT5 seems to act as an oncogene in the progression of BC. Our data suggest that CircPRMT5 may be used as a biomarker for the diagnosis, prognosis evaluation, and targeted therapy of breast cancer.

Finally, we observed that treatment of LLY-283 alleviated neurological deficits and reduced infarct volume in the MCAO/R mice. Taken together, PRMT5 may be a potential therapeutic target for cerebral I/R injury.

CircPRMT5 seems to act as an oncogene in the progression of BC. Our data suggest that CircPRMT5 may be used as a biomarker for the diagnosis, prognosis evaluation and targeted therapy of breast cancer.

AGX323 demonstrated potentially best-in-class activity in PRMT5 dependent human solid cancer models and exhibited excellent drug-like properties. IND enabling studies are currently planned.