Targeting PRMTs with small-molecule inhibitors: a comprehensive review

Area of Science:

• Epigenetics and Molecular Biology
• Medicinal Chemistry
• Pharmacology

Background:

• Protein arginine methyltransferases (PRMTs) catalyze arginine methylation, a post-translational modification regulating crucial cellular functions.
• Aberrant PRMT activity is implicated in tumorigenesis and other diseases, making them attractive therapeutic targets.
• Small-molecule modulators of PRMTs have been developed to target their catalytic machinery.

Purpose of the Study:

• To review the current landscape of small-molecule PRMT modulators.
• To highlight diverse chemotypes, binding modes, and structure-activity relationships (SARs) for various PRMT isoforms.
• To discuss emerging strategies and compounds in preclinical or clinical development for targeted epigenetic therapies.

Main Methods:

• Literature review of medicinal chemistry campaigns and drug discovery efforts.
• Analysis of different inhibitor classes targeting PRMTs, including SAM-competitive, substrate-pocket, and bisubstrate inhibitors.
• Examination of innovative approaches like MTA-cooperative inhibitors and targeted protein degradation (TPD).

Main Results:

• Identification of potent small-molecule inhibitors for PRMT isoforms, particularly PRMT5, with promising cellular activity and pharmacological profiles.
• Development of chemical probes for studying PRMT1, PRMT4 (CARM1), PRMT6, and PRMT7.
• Emergence of novel therapeutic strategies, including MTA-cooperative inhibitors for MTAP-deleted tumors and TPD approaches.

Conclusions:

• Small-molecule PRMT modulation has rapidly evolved, offering a growing arsenal for targeted epigenetic therapies.
• Compounds targeting PRMTs have advanced to preclinical and clinical evaluations, demonstrating therapeutic potential.
• Continued research in PRMT-directed medicinal chemistry is crucial for improving selectivity and therapeutic applicability in disease treatment.