Pande Vineet, Sun Weimei, Beke Lijs, Berthelot Didier, Brehmer Dirk, Brown David, Corbera Jordi, Irving Steve, Meerpoel Lieven, Nys Thomas, Parade Marc, Robinson Colin, Sommen Cois, Viellevoye Marcel, Wu Tongfei, Thuring Jan Willem
Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
Janssen Research and Development, 1400 McKean Road, Spring House, Pennsylvania 19002, United States.
ACS Med Chem Lett. 2020 Sep 28;11(11):2227-2231. doi: 10.1021/acsmedchemlett.0c00355. eCollection 2020 Nov 12.
Protein arginine methyltransferase 5 (PRMT5) is an enzyme that can symmetrically dimethylate arginine residues in histones and nonhistone proteins by using -adenosyl methionine (SAM) as the methyl donating cofactor. We have designed a library of SAM analogues and discovered potent, cell-active, and selective spiro diamines as inhibitors of the enzymatic function of PRMT5. Crystallographic studies confirmed a very interesting binding mode, involving protein flexibility, where both the cofactor pocket and part of substrate binding site are occupied by these inhibitors.
蛋白质精氨酸甲基转移酶5（PRMT5）是一种能够利用S-腺苷甲硫氨酸（SAM）作为甲基供体辅因子，对组蛋白和非组蛋白中的精氨酸残基进行对称二甲基化的酶。我们设计了一个SAM类似物文库，并发现了强效、具有细胞活性且具有选择性的螺二胺作为PRMT5酶功能的抑制剂。晶体学研究证实了一种非常有趣的结合模式，涉及蛋白质的灵活性，其中辅因子口袋和部分底物结合位点都被这些抑制剂占据。
