Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Merck & Co., Inc., 770 Sumneytown Pike, Lansdale, Pennsylvania 19446, United States.
J Med Chem. 2021 Apr 8;64(7):3911-3939. doi: 10.1021/acs.jmedchem.0c02083. Epub 2021 Mar 23.
Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the post-translational symmetric dimethylation of protein substrates. PRMT5 plays a critical role in regulating biological processes including transcription, cell cycle progression, RNA splicing, and DNA repair. As such, dysregulation of PRMT5 activity is implicated in the development and progression of multiple cancers and is a target of growing clinical interest. Described herein are the structure-based drug designs, robust synthetic efforts, and lead optimization strategies toward the identification of two novel 5,5-fused bicyclic nucleoside-derived classes of potent and efficacious PRMT5 inhibitors. Utilization of compound docking and strain energy calculations inspired novel designs, and the development of flexible synthetic approaches enabled access to complex chemotypes with five contiguous stereocenters. Additional efforts in balancing bioavailability, solubility, potency, and CYP3A4 inhibition led to the identification of diverse lead compounds with favorable profiles, promising activity, and low human dose projections.
精氨酸甲基转移酶 5（PRMT5）是一种 II 型精氨酸甲基转移酶，能够催化蛋白质底物的翻译后对称二甲基化。PRMT5 在调节转录、细胞周期进程、RNA 剪接和 DNA 修复等生物学过程中发挥着关键作用。因此，PRMT5 活性的失调与多种癌症的发生和发展有关，并且是日益受到关注的临床治疗靶点。本文描述了基于结构的药物设计、稳健的合成努力和先导化合物优化策略，旨在鉴定两种新型的 5,5-稠合双环核苷衍生的强效和有效的 PRMT5 抑制剂。化合物对接和应变能计算的应用启发了新的设计，灵活的合成方法的开发使得能够获得具有五个连续手性中心的复杂化学型。在平衡生物利用度、溶解度、效力和 CYP3A4 抑制方面的进一步努力，导致了具有良好特征、有前景的活性和低人体剂量预测的各种先导化合物的鉴定。
