The SET and MYND domain containing protein 2 (SMYD2) is a member of the lysine methyltransferases (KMT) family of enzymes which catalyze the methylation of histone and non-histone proteins, serving as regulators of gene transcription and cellular physiology. SMYD2 is one of several reportedly oncogenic methyltransferases, and has been shown to repress functional activity of the tumor suppressor proteins p53 and Rb, implicating it as an attractive drug target. High throughput screening of the AstraZeneca corporate compound collection led to identification of several distinct substrate competitive chemical series. A ‘hit-to-lead’ effort was undertaken, employing structure-based design, which culminated in the creation of a bi-arylpiperazine series as potent and selective SMYD2 inhibitors. The evolution, SAR and synthesis of exemplars from this series will be discussed. These inhibitors provide valuable tools for probing the cell biology of SMYD2 and its role in disease states.

Discovery and synthesis of substrate competitive SMYD2 inhibitors

250th National Meeting (2015)

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