title: Structural basis of substrate methylation and inhibition of SMYD2.
abstract: Protein lysine methyltransferases are important regulators of epigenetic signaling. These enzymes catalyze the transfer of donor methyl groups from S-adenosylmethionine to specific acceptor lysines on histones, leading to changes in chromatin structure and transcriptional regulation. These enzymes also methylate nonhistone protein substrates, revealing an additional mechanism to regulate cellular physiology. The oncogenic protein SMYD2 represses the functional activities of the tumor suppressor proteins p53 and Rb, making it an attractive drug target. Here we report the discovery of AZ505, a potent and selective inhibitor of SMYD2 that was identified from a high throughput chemical screen. We also present the crystal structures of SMYD2 with p53 substrate and product peptides, and notably, in complex with AZ505. This substrate competitive inhibitor is bound in the peptide binding groove of SMYD2. These results have implications for the development of SMYD2 inhibitors, and indicate the potential for developing novel therapies targeting this target class.
authors.affiliation: DECS Structural Chemistry, AstraZeneca, Waltham, MA 02451, USA. andrew.ferguson@astrazeneca.com
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Ferguson
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Larsen
authors.forename: Tina
authors.initials: T
authors.lastname: Howard
authors.forename: Hannah
authors.initials: H
authors.lastname: Pollard
authors.forename: Isabelle
authors.initials: I
authors.lastname: Green
authors.forename: Christie
authors.initials: C
authors.lastname: Grande
authors.forename: Tony
authors.initials: T
authors.lastname: Cheung
authors.forename: Renee
authors.initials: R
authors.lastname: Garcia-Arenas
authors.forename: Scott
authors.initials: S
authors.lastname: Cowen
authors.forename: Jiaquan
authors.initials: J
authors.lastname: Wu
authors.forename: Robert
authors.initials: R
authors.lastname: Godin
authors.forename: Huawei
authors.initials: H
authors.lastname: Chen
authors.forename: Nicholas
authors.initials: N
authors.lastname: Keen
mesh_terms: D020816:Amino Acid Motifs; D000970:Antineoplastic Agents / Q000737:chemistry*; D048588:Benzoxazines / Q000737:chemistry*; D001665:Binding Sites; D020134:Catalytic Domain; D003067:Coenzymes / Q000737:chemistry; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D057075:Enzyme Assays; D004938:Esophageal Neoplasms; D057166:High-Throughput Screening Assays; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008745:Methylation; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry; D011485:Protein Binding; D013499:Surface Properties; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: C568821:AZ 505; D000970:Antineoplastic Agents; D048588:Benzoxazines; D003067:Coenzymes; D010446:Peptide Fragments; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D015091:beta-Alanine; D011495:Histone-Lysine N-Methyltransferase; C512569:SMYD2 protein, human