TNG462的发现：一种高效且选择性的MTA协同PRMT5抑制剂，用于靶向缺失型癌症。

Cottrell Kevin M, Briggs Kimberly J, Tsai Alice, Tonini Matthew R, Whittington Douglas A, Gong Shanzhong, Liang Colin, McCarren Patrick, Zhang Minjie, Zhang Wenhai, Huang Alan, Maxwell John P

Tango Therapeutics, Boston, Massachusetts 02215, United States.

J Med Chem. 2025 Mar 13;68(5):5097-5119. doi: 10.1021/acs.jmedchem.4c03067. Epub 2025 Mar 4.

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 -deleted cancer cells by binding to and inhibiting PRMT5 cooperatively with MTA, which is present in elevated concentrations in -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 -deleted cancers and is currently in Phase I/II clinical trials.

编码MTAP的基因是癌症中最常被删除的基因之一，在所有人类癌症中约占10 - 15%。我们之前描述了TNG908的发现，这是一种可穿透血脑屏障的临床阶段化合物，它通过与MTA协同结合并抑制PRMT5来选择性靶向MTAP缺失的癌细胞，而MTA在MTAP缺失的细胞中浓度升高。在此，我们描述了TNG462的发现，它是一种更有效、更具选择性的MTA协同PRMT5抑制剂，具有改善的药物代谢动力学性质，对MTAP缺失的癌症具有选择性，目前正处于I/II期临床试验阶段。