PRMT5 is the primary type II arginine methyltransferase responsible for symmetric dimethylation of protein arginine residues and plays an important role in tumorigenesis through post-translational modification of cytoplasmic and nuclear substrates. The discovery of adenosine as an efficient inhibitor of PRMT5 catalyzed a design and synthesis 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 the identification and characterization of PF-06855800, a SAM competitive, brain-restricted lead molecule with antiproliferative activity in both in vitro and in vivo models.

Discovery of SAM competitive, brain-restricted PRMT5 inhibitors with potent antitumor activity

255th National Meeting (2018)

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