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Structure-Guided Discovery of Novel Highly Potent and Selective MTA-Cooperative PRMT5 Inhibitors
Chuping Huang1, Min Liang2, Ping Zhang2
1Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China.
Abstract:
Methylthioadenosine (MTA) accumulation inhibits the protein arginine methyltransferase 5 (PRMT5), rendering cancers harboring methylthioadenosine phosphorylase (MTAP) deletion vulnerable; thus, PRMT5 inhibitors hold promise for treating these cancers. In this letter, a structure-guided design approach yielded many novel highly potent and selective MTA-cooperative PRMT5 inhibitors featuring a core structure of 4-amino-N-((5-ethynylpyridin-2-yl)-methyl)-1-methyl-1H-pyrazolo-[4,3-c]-quinoline-8-carboxamide. Among them, compound 27 demonstrated significant inhibitory activity and selectivity against HCT116 MTAP-del cells. Further biological evaluations demonstrated that this compound exerts potent inhibitory effects across multiple MTAP-null cancer cell lines, alongside robust enzymatic inhibition and favorable pharmacokinetic profiles consistent with drug-like properties. Notably, compound 27 displayed prominent in vivo antitumor potency in a HCT116 MTAP-/- CDX model. Collectively, these results establish compound 27 as a highly effective and selective MTA-cooperative PRMT5 inhibitor, presenting a promising candidate for future therapeutic development.
Insights
Novel PRMT5 inhibitors targeting MTAP-deleted cancers show promise. Compound 27, a potent MTA-cooperative PRMT5 inhibitor, demonstrates significant antitumor activity in preclinical models, offering a potential new therapy for these specific cancers.
Area of Science:
- Oncology
- Medicinal Chemistry
- Pharmacology
Background:
- Methylthioadenosine (MTA) accumulation inhibits PRMT5, creating a vulnerability in cancers with MTAP deletion.
- PRMT5 inhibitors are a promising therapeutic strategy for MTAP-deleted cancers.
Purpose of the Study:
- To design and identify novel, potent, and selective MTA-cooperative PRMT5 inhibitors.
- To evaluate the therapeutic potential of a lead compound (compound 27) in MTAP-deleted cancer models.
Main Methods:
- Structure-guided design approach to synthesize novel PRMT5 inhibitors.
- In vitro enzymatic assays and cell-based assays using MTAP-deleted cancer cell lines (e.g., HCT116).
- In vivo efficacy studies in a HCT116 MTAP-/- CDX model and pharmacokinetic profiling.
Main Results:
- Identification of novel 4-amino-N-((5-ethynylpyridin-2-yl)-methyl)-1-methyl-1H-pyrazolo-[4,3-c]-quinoline-8-carboxamide derivatives as PRMT5 inhibitors.
- Compound 27 exhibited potent and selective inhibition of PRMT5 in MTAP-deleted cancer cells.
- Compound 27 demonstrated significant in vivo antitumor activity and favorable pharmacokinetic properties.
Conclusions:
- Compound 27 is a highly effective and selective MTA-cooperative PRMT5 inhibitor.
- The findings establish compound 27 as a promising therapeutic candidate for MTAP-deleted cancers.
- Further clinical development of compound 27 is warranted for treating specific cancer types.
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