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

Producción científica: Artículo en revista indizadaArtículorevisión exhaustiva

20 Citas (Scopus)

Resumen

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.
Idioma originalInglés
Páginas (desde-hasta)3911-3939
Número de páginas29
PublicaciónJournal of Medicinal Chemistry
Volumen64
N.º7
Fecha en línea anticipadamar 2021
DOI
EstadoPublicada - 8 abr 2021
Publicado de forma externa

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