A First-in-Class, Highly Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 6

Area of Science:

• Biochemistry
• Epigenetics
• Chemical Biology

Background:

• Protein arginine methyltransferase 6 (PRMT6) is implicated in critical biological processes and various cancers.
• A highly selective inhibitor for PRMT6 has been lacking, hindering research into its functions.

Purpose of the Study:

• To discover and characterize the first-in-class, highly selective allosteric inhibitor of PRMT6.
• To provide a chemical tool for investigating PRMT6's role in biological systems.

Main Methods:

• Discovery and characterization of a novel small molecule inhibitor, (R)-2 (SGC6870).
• Biochemical assays to determine potency (IC50) and selectivity against various methyltransferases and other targets.
• Crystal structure determination of the PRMT6-(R)-2 complex.
• Cellular assays to assess PRMT6 inhibition.
• Enantiomeric comparison using (S)-2 (SGC6870N) as a negative control.

Main Results:

• Identification of (R)-2 as a potent PRMT6 inhibitor with an IC50 of 77 ± 6 nM.
• Demonstration of outstanding selectivity for PRMT6 over a wide range of related and unrelated targets.
• Elucidation of the allosteric binding mode through crystal structure and kinetic studies, revealing a unique induced pocket.
• (R)-2 effectively inhibits PRMT6 activity in cellular contexts.
• The inactive enantiomer, (S)-2, serves as a reliable negative control.

Conclusions:

• (R)-2 represents the first highly selective, allosteric inhibitor of PRMT6.
• This compound is a well-characterized chemical probe with significant potential for advancing the understanding of PRMT6 biology.
• (R)-2 provides a valuable tool for exploring PRMT6's involvement in both normal physiological functions and disease states, particularly cancer.