Discovery of 6-aryl-azabenzimidazoles that inhibit the TBK1/IKK-ε kinases.

The discovery and optimization of a series of 6-aryl-azabenzimidazole inhibitors of TBK1 and IKK-ε is described. Various internal azabenzimidazole leads and reported TBK1/IKK-ε inhibitors were docked into a TBK1 homology model. The resulting overlays inspired a focused screen of 6-substituted azabenzimidazoles against TBK1/IKK-ε. This screen resulted in initial hit compound 3. The TBK1/IKK-ε enzyme and cell potency of this compound was further improved using structure guided drug design. Systematic exploration of the C6 aryl group led to compound 19, a potent inhibitor of TBK1 with selectivity against cell cycle kinases CDK2 and Aurora B. Further elaboration and optimization gave compound 25, a single digit nM inhibitor of TBK1. These compounds may serve as in vitro probes to evaluate TBK1/IKK-ε as an oncology target.

Design, Synthesis, and Biological Activity of Substrate Competitive SMYD2 Inhibitors.

Protein lysine methyltransferases (KMTs) have emerged as important regulators of epigenetic signaling. These enzymes catalyze the transfer of donor methyl groups from the cofactor S-adenosylmethionine to specific acceptor lysine residues on histones, leading to changes in chromatin structure and transcriptional regulation. These enzymes also methylate an array of nonhistone proteins, suggesting additional mechanisms by which they influence cellular physiology. SMYD2 is reported to be an oncogenic methyltransferase that represses the functional activity of the tumor suppressor proteins p53 and RB. HTS screening led to identification of five distinct substrate-competitive chemical series. Determination of liganded crystal structures of SMYD2 contributed significantly to "hit-to-lead" design efforts, culminating in the creation of potent and selective inhibitors that were used to understand the functional consequences of SMYD2 inhibition. Taken together, these results have broad implications for inhibitor design against KMTs and clearly demonstrate the potential for developing novel therapies against these enzymes.