Discovery of TNG462: A Highly Potent and Selective MTA-Cooperative PRMT5 Inhibitor to Target Cancers with MTAP Deletion

作者：Kevin M. Cottrell, Kimberly J. Briggs, Alice Tsai, Matthew R. Tonini, Douglas A. Whittington, Shanzhong Gong, Colin Liang, Patrick McCarren, Minjie Zhang, Wenhai Zhang, Alan Huang, John P. Maxwell · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.4c03067 · 被引用次数：32 · 研究领域：Cancer-related gene regulation、Synthesis and Catalytic Reactions

High Resolution Image Download MS PowerPoint Slide The gene encoding for MTAP is one of the most commonly deleted genes in cancer, occurring in approximately 10–15% of all human cancer. We have previously described the discovery of TNG908, a brain-penetrant clinical-stage compound that selectively targets MTAP -deleted cancer cells by binding to and inhibiting PRMT5 cooperatively with MTA, which is present in elevated concentrations in MTAP -deleted cells. Herein we describe the discovery of TNG462, a more potent and selective MTA-cooperative PRMT5 inhibitor with improved DMPK properties that is selective for MTAP -deleted cancers and is currently in Phase I/II clinical trials.