Abstract

Protein Methyltransferases and Drug Discovery

Ann Boriack-Sjodin, Director, Epizyme Inc

SMYD3 (Set and Mynd Domain containing 3) is a lysine methyltransferase overexpressed in several cancer types including breast, prostrate, pancreatic, and lung, and this overexpression is associated with poor clinical prognosis. Genetic knockdown of SMYD3 by shRNA has been shown to decrease proliferation in a range of cancer cell lines suggesting that inhibition of SMYD3 may have therapeutic utility. In this presentation the discovery and optimization of a novel series of sulfonamides and sulfamides with SMYD3 inhibitory activity will be described. The compounds are potent in both biochemical and in-cell western (ICW) assays and selective for SMYD3 over other protein methyltransferase enzymes, including SMYD2. Several crystal structures of these compounds in complex with SMYD3 and the nucleotide substrate, S-adenosylmethionine have been solved and show the molecules bind in the lysine channel and extend into the SMYD3 peptide binding site. Optimization of this inhibitor series resulted in compounds with good oral bioavailability and PK properties that are suitable for both in vitro and in vivo use. The effects of these compounds in cancer cell lines and comparison with gene ablation technologies will be described.