From DNA-Encoded Library Screening to AM-9747: An MTA-Cooperative PRMT5 Inhibitor with Potent Oral In Vivo Efficacy.

Area of Science:

• Oncology
• Pharmacology
• Structural Biology

Background:

• Methylthioadenosine phosphorylase (MTAP)-deleted cancers exhibit a vulnerability due to the accumulation of methylthioadenosine (MTA) and subsequent inhibition of the methyltransferase enzyme PRMT5.
• Targeting PRMT5 presents a therapeutic strategy for MTAP-deleted malignancies.

Purpose of the Study:

• To discover and optimize novel inhibitors of PRMT5 that exploit the MTAP-deleted cancer vulnerability.
• To characterize the mechanism of action and preclinical efficacy of the optimized PRMT5 inhibitor.

Main Methods:

• Discovery and lead optimization of quinolin-2-amine derivatives targeting PRMT5.
• X-ray crystallography to elucidate the binding mode of the inhibitor with PRMT5 and MTA.
• In vitro assessment of PRMT5 inhibition and cell viability in MTAP-deleted versus wild-type cancer cells.
• In vivo evaluation of compound AM-9747 in mouse xenograft models for tolerability, pharmacodynamics, and efficacy.

Main Results:

• A novel quinolin-2-amine derivative, AM-9747, was identified that binds PRMT5 and MTA, forming a catalytically inhibited ternary complex.
• X-ray crystallography confirmed binding of AM-9747 to PRMT5 at glutamate-444 with concurrent hydrophobic interaction with MTA.
• AM-9747 selectively inhibits PRMT5-mediated symmetric dimethylation of arginine residues, potently reducing cell viability in MTAP-deleted cells.
• Once-daily oral administration of AM-9747 in mouse xenografts was well tolerated, demonstrating dose-dependent inhibition of symmetric dimethylation and significant tumor growth inhibition in MTAP-deleted xenografts, with no effect on MTAP-WT xenografts.

Conclusions:

• AM-9747 is a potent and selective PRMT5 inhibitor with promising preclinical efficacy against MTAP-deleted cancers.
• The drug's mechanism involves cooperative binding to PRMT5 and MTA, leading to catalytic inhibition.
• AM-9747 demonstrates good tolerability and therapeutic potential for treating MTAP-deleted tumors.