The Discovery of Two Novel Classes of 5,5-Bicyclic Nucleoside-Derived PRMT5 Inhibitors for the Treatment of Cancer

Ryan Quiroz, Michael H. Reutershan, Sebastian E. Schneider, David Sloman, Brian M. Lacey, Brooke M. Swalm, Charles S. Yeung, Craig Gibeau, Daniel S. Spellman, Danica A. Rankic, Dapeng Chen, David Witter, Doug Linn, Erik Munsell, Guo Feng, Haiyan Xu, Jonathan M. E. Hughes, Jongwon Lim, Josep Sauri, Kristin GeddesMurray Wan, My Sam Mansueto, Nicole E. Follmer, Patrick S. Fier, Phieng Siliphaivanh, Pierre Daublain, Rachel L. Palte, Robert P. Hayes, Sandra Lee, Shuhei Kawamura, Steven Silverman, Sulagna Sanyal, Timothy J. Henderson, Yingchun Ye, Yuanwei Gao, Benjamin Nicholson, Michelle R. Machacek

Research output: Indexed journal article Articlepeer-review

20 Citations (Scopus)

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 in vivo activity, and low human dose projections.
Original languageEnglish
Pages (from-to)3911-3939
Number of pages29
JournalJournal of Medicinal Chemistry
Volume64
Issue number7
Early online dateMar 2021
DOIs
Publication statusPublished - 8 Apr 2021
Externally publishedYes

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