MTA-Cooperative PRMT5 Inhibitors: Mechanism Switching Through Structure-Based Design

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Deletion of the methylthioadenosine phosphorylase (MTAP) gene results in the accumulation of its substrate, methylthioadenosine (MTA).
• MTA competes with S-adenosyl-l-methionine (SAM) for binding to PRMT5, an enzyme crucial in cancer cell proliferation.
• Selective inhibition of the PRMT5•MTA complex over the PRMT5•SAM complex presents a strategy for targeting MTAP-deleted cancers.

Purpose of the Study:

• To discover novel compounds that selectively target cancer cells with MTAP deletion.
• To switch the binding mechanism of PRMT5 inhibitors from SAM-cooperative to MTA-cooperative.
• To achieve selective killing of MTAP-deleted cancer cells through structure-based drug design.

Main Methods:

• Employed structure-based drug design to identify novel chemical entities.
• Focused on compounds that occupy the SAM binding pocket of PRMT5 unoccupied by MTA.
• Engineered compounds to form hydrogen bonds with Arg368 in the PRMT5 active site.

Main Results:

• Discovered novel compounds that bind to PRMT5 in an MTA-cooperative manner.
• These compounds occupy a specific region of the SAM binding pocket, distinct from MTA binding.
• The designed compounds enable selective targeting of MTAP-deleted cancer cells.

Conclusions:

• Successfully developed novel PRMT5 inhibitors with an MTA-cooperative binding mechanism.
• These inhibitors selectively target cancer cells harboring MTAP deletions.
• This represents a promising new therapeutic approach for MTAP-deleted cancers.