Targeting PRMTs with small-molecule inhibitors: a comprehensive review

Area of Science:

• Epigenetics and Molecular Biology
• Medicinal Chemistry
• Pharmacology

Background:

• Protein arginine methyltransferases (PRMTs) are SAM-dependent enzymes catalyzing arginine methylation, a post-translational modification crucial for cellular processes.
• Aberrant PRMT activity is implicated in tumorigenesis and other diseases, making them attractive targets for drug development.
• Diverse cellular functions regulated by PRMTs include chromatin dynamics, transcriptional control, RNA metabolism, and DNA damage response.

Purpose of the Study:

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

Main Methods:

• Review of medicinal chemistry campaigns and literature on small-molecule PRMT modulators.
• Analysis of distinct inhibitor classes targeting different binding regions within PRMTs.
• Examination of structure-activity relationships (SARs) and pharmacological profiles of identified compounds.

Main Results:

• Identification of various small-molecule inhibitor classes, including SAM-competitive, substrate-pocket binders, and bisubstrate analogues.
• Development of potent and selective modulators for PRMT isoforms like PRMT5, PRMT1, PRMT4 (CARM1), PRMT6, and PRMT7.
• Emergence of innovative strategies such as MTA-cooperative inhibitors and targeted protein degradation (TPD) approaches.

Conclusions:

• Small-molecule modulation of PRMTs has rapidly evolved, offering promising avenues for targeted epigenetic therapies.
• Compounds targeting PRMTs show potential for treating cancer and other pathological conditions.
• Ongoing research focuses on improving inhibitor selectivity and therapeutic applicability for enhanced clinical translation.