MTA-cooperative PRMT5 inhibitors from cofactor-directed DNA-encoded library screens

• 成果类型: Article
• 署名作者: Anderssona, Jan; Cowlanda, Sanne; Vestergaarda, Mikkel; Yangb, Yajing; Liub, Siyuan; Fangc, Xie; Mukundc, Susmith; Ghimire-Rijalb, Sudipa; Carterb, Chris; Chungb, Grace; Jacsoa, Tomas; Sarvarya, Ian; Hughesb, Paul E.; Gouliaeva, Alex; Paytonb, Marc; Belmontesb, Brian; Caenepeelb, Sean; Francha, Thomas; Glada, Sanne; Husemoena, Birgitte; Nielsena, Soren Jensby
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14535
• DOI: 10.1073/pnas.2425052122
• 发表日期: 2025-05-20
• 关键词: arginine methyltransferase; cancer; jnj-64619178; genes

摘要

Methylthioadenosine phosphorylase (MTAP) gene deletions are frequent in human cancers. Loss ofMTAP leads to significantly increased cellular levels of methylthioadenosine (MTA), a cellular metabolite and specific inhibitor of the cell-essential enzyme Protein Arginine Methyltransferase-5 (PRMT5). Using a cofactor-directed screening strategy and DNA-encoded libraries, we identify a class of PRMT5 inhibitors that cooperatively inhibit PRMT5 in the presence of MTA. An optimized inhibitor, AM-9934, selectively inhibits PRMT5 in MTAP-deleted cells and in transplanted tumors while sparing MTAP-expressing counterparts, leading to specific suppression of viability in MTAP-deleted cells. Structural studies show that AM-9934 occupies the arginine substrate pocket of MTA-bound PRMT5. This study introduces a broadly applicable method for directed DNA-encoded library screening toward a desired mechanistic outcome and highlights MTA-selective PRMT5 inhibition as an attractive therapeutic strategy with a potentially broad therapeutic index in patients with MTAP-deleted cancers.