Abstract 4857: Discovery of PF-06855800, a SAM Competitive PRMT5 Inhibitor with Potent Antitumor Activity

Abstract Protein arginine methyltransferase 5 (PRMT5) is the primary type II arginine methyltransferase responsible for symmetric dimethylation of protein arginine residues. PRMT5 utilizes S-adenosylmethionine (SAM) to methylate a number of cytoplasmic and nuclear substrates that are involved in tumorigenesis. A number of these substrates affect a variety of biologic functions including RNA splicing, transcriptional regulation and translation, all of which are dysregulated in cancer. The discovery of adenosine as an efficient inhibitor of PRMT5 catalyzed a medicinal chemistry effort aimed at nucleoside optimization. Protein structure-based and ligand property-based design were combined to deliver molecules with desirable potency, selectivity and ADME properties. Here we will describe a series of deazapurine nucleoside analogues that culminate in the identification of PF-06855800, a SAM competitive PRMT5 inhibitor with antiproliferative activity in both in vitro and in vivo models. Citation Format: Indrawan J. Mcalpine, John Tatlock, Joseph Billitti, John Braganza, Alexei Brooun, Deng Ya-Li, Brad Hirakawa, Kristen Jensen-Pergakes, Robert Kumpf, Wei Liu, Karen Maegley, Michele McTigue, Ryan Patman, Eugene Rui, Stephanie Scales, Noah Spiegel, Michelle Tran-Dubé, Fen Wang, Zhenxiong Wang, Shinji Yamazaki, Tao Zhang, Martin Wythes. Discovery of PF-06855800, a SAM competitive PRMT5 inhibitor with potent antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4857.