7KID

PRMT5:MEP50 Complexed with 5,5-Bicyclic Inhibitor Compound 72

7KID の概要

• エントリーDOI: 10.2210/pdb7kid/pdb
• 分子名称: Protein arginine N-methyltransferase 5, Methylosome protein 50, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 112358.78

構造登録者

Palte, R.L. (登録日: 2020-10-23, 公開日: 2021-04-21, 最終更新日: 2024-10-09)

主引用文献

Quiroz, R.V.,Reutershan, M.H.,Schneider, S.E.,Sloman, D.,Lacey, B.M.,Swalm, B.M.,Yeung, C.S.,Gibeau, C.,Spellman, D.S.,Rankic, D.A.,Chen, D.,Witter, D.,Linn, D.,Munsell, E.,Feng, G.,Xu, H.,Hughes, J.M.E.,Lim, J.,Sauri, J.,Geddes, K.,Wan, M.,Mansueto, M.S.,Follmer, N.E.,Fier, P.S.,Siliphaivanh, P.,Daublain, P.,Palte, R.L.,Hayes, R.P.,Lee, S.,Kawamura, S.,Silverman, S.,Sanyal, S.,Henderson, T.J.,Ye, Y.,Gao, Y.,Nicholson, B.,Machacek, M.R.
The Discovery of Two Novel Classes of 5,5-Bicyclic Nucleoside-Derived PRMT5 Inhibitors for the Treatment of Cancer.
J.Med.Chem., 64:3911-3939, 2021

PubMed Abstract: 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.

PubMed: 33755451
DOI: 10.1021/acs.jmedchem.0c02083

実験手法

X-RAY DIFFRACTION (2.5 Å)