In the human kinome there are more than 500 protein kinases, but only about 10% have been extensively studied, showing the need for a better kinase inhibitor pipeline. The understudied kinase SLK has been linked to cell multiplication processes and studies suggest that SLK inhibition might be able to decrease the invasive and metastatic process. According to our previous in vitro screening, a maleimide scaffold provides an interesting starting point towards an SLK inhibitor. A co-crystal structure of the first SLK/maleimide complex was obtained at 1.6 Å resolution and this information was used to design new compounds by an automated computational approach, selecting the best ranked molecules to be synthesized. The automated virtual screening pipeline used a virtual library (&gt;10,000) of new maleimides derived from commercially available building blocks (Wuxi and Sigma-Aldrich), the co-crystal structure, docking and scoring (Schrödinger molecular modeling package) to get new insights into molecules that could have improved potency and selectivity (Figure 1). Based on the docking score results and visual inspection of the ligand-target interactions involved in the binding site (Figure 2), a diverse selection of new maleimide compounds were chosen and were synthesized using a four-step synthetic route to be tested in SLK binding assays. The prototype maleimide has nM affinity with the kinase target. The compounds designed had good docking scores and were successfully synthesized (reasonable to good yields). The inhibition assays are ongoing.

Structure-based design of inhibitors for STE20-like kinase (SLK)

256th National Meeting (2018)

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