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TNG908的发现：一种具有选择性、可穿透血脑屏障、与MTA协同作用的PRMT5抑制剂，对Δ-缺失型癌症具有合成致死性。

Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with -Deleted Cancers.

作者信息

Cottrell Kevin M, Briggs Kimberly J, Whittington Douglas A, Jahic Haris, Ali Janid A, Davis Charles B, Gong Shanzhong, Gotur Deepali, Gu Lina, McCarren Patrick, Tonini Matthew R, Tsai Alice, Wilker Erik W, Yuan Hongling, Zhang Minjie, Zhang Wenhai, Huang Alan, Maxwell John P

机构信息

Tango Therapeutics, Boston, Massachusetts 02215, United States.

出版信息

J Med Chem. 2024 Apr 25;67(8):6064-6080. doi: 10.1021/acs.jmedchem.4c00133. Epub 2024 Apr 10.

DOI:10.1021/acs.jmedchem.4c00133
PMID:38595098
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11056935/
Abstract

It has been shown that PRMT5 inhibition by small molecules can selectively kill cancer cells with homozygous deletion of the gene if the inhibitors can leverage the consequence of deletion, namely, accumulation of the MTAP substrate MTA. Herein, we describe the discovery of TNG908, a potent inhibitor that binds the PRMT5·MTA complex, leading to 15-fold-selective killing of -deleted (MTAP-null) cells compared to intact (MTAP WT) cells. TNG908 shows selective antitumor activity when dosed orally in mouse xenograft models, and its physicochemical properties are amenable for crossing the blood-brain barrier (BBB), supporting clinical study for the treatment of both CNS and non-CNS tumors with loss.

摘要

研究表明，如果小分子对PRMT5的抑制作用能够利用该基因缺失的后果，即MTAP底物MTA的积累，那么这些小分子就可以选择性地杀死该基因纯合缺失的癌细胞。在此，我们描述了TNG908的发现，它是一种强效抑制剂，可与PRMT5·MTA复合物结合，与完整（MTAP野生型）细胞相比，对缺失（MTAP缺失）细胞具有15倍的选择性杀伤作用。在小鼠异种移植模型中口服给药时，TNG908表现出选择性抗肿瘤活性，其物理化学性质有利于穿过血脑屏障（BBB），支持针对中枢神经系统和非中枢神经系统肿瘤缺失的临床研究。

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Arginine Methylation: The Coming of Age.
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Discovery of a Potent and Selective Protein Arginine Methyltransferase 5 (PRMT5) PROTAC Degrader.一种强效且选择性的蛋白质精氨酸甲基转移酶5（PRMT5）PROTAC降解剂的发现。
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PRMT5 inhibitors: Therapeutic potential in pancreatic cancer.蛋白精氨酸甲基转移酶5（PRMT5）抑制剂：在胰腺癌中的治疗潜力
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