Novel Efficient Multistage Lead Optimization Pipeline Experimentally Validated for DYRK1B Selective Inhibitors.

In addition to general challenges in drug discovery such as the identification of lead compounds in time- and cost-effective ways, specific challenges also exist. Particularly, it is necessary to develop pharmacological inhibitors that effectively discriminate between closely related molecular targets. DYRK1B kinase is considered a valuable target for cancer-specific mono- or combination chemotherapy; however, the inhibition of its closely related DYRK1A kinase is not beneficial. Existing inhibitors target both kinases with essentially the same efficiency, and the unavailability of the DYRK1B crystal structure makes the discovery of DYRK1B-specific inhibitors even more challenging. Here, we propose a novel multi-stage compound discovery pipeline aimed at in silico identification of both potent and selective small molecules from a large set of initial candidates. The method uses structure-based docking and ligand-based quantitative structure-activity relationship modeling. This approach allowed us to identify lead and runner-up small-molecule compounds targeting DYRK1B with high efficiency and specificity.