Salt-Inducible Kinase 2 (Sik2) is a centrosome kinase that has recently been reported as a potential target for therapy in ovarian cancer. As there was no structure available for SIK2 at the time of this work, we generated a three plausible homology models based on a single template, Mark3PAR-1. Kinase targeted libraries from several vendors were screened against these homology modes, but this resulted in very few structures that could adopt typical kinase binding modes. This led us to seek an alternative strategy for the designs. Aurora A kinase was identified as a possible structural template during the homology building process and one series of inhibitors of that kinase were selected and utilized as a starting point for design of Sik2 inhibitors. There appears to be less room available in the ATP binding site of Sik2 and many of the attached groups for the Aurora inhibitors would tend to bump into residues if not modified substantially. Therefore, one side of the structure was reduced in size so that it would better interact with nearby residues. A library was generated based on the modified template and the enumerated library was docked using Surflex and Glide XP with MM-GBSA post-processing. The resulting scores and structures from docking were fed into a workflow that combined the results and calculated ADME style parameters for each compound. A series of filtering cutoffs led to the top scoring compounds. Both docking programs led to reasonable binding modes expected of typical kinase inhibitors. There were eleven compounds that met the analysis criteria and five of those were synthesized and tested for inhibition of phosphorylation of SIK2. The design, synthesis, and biological testing of these compounds will be reported.

Structure-based drug design and synthesis of salt-inducible kinase 2 (SIK 2) inhibitors

246th National Meeting (2013)

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