DYRK1A is a cell-cycle regulator which has been implicated as an important drug target in various therapeutic areas, including neurological disorders, oncology, and diabetes. In order to identify a novel DYRK1A inhibitor, we constructed a homology model of DYRK1A in the inactive, DFG-out conformation, using a new method called DFGmodel developed in our group. Virtual screening of 2.2 million lead-like compounds from the ZINC database, followed by in vitro testing of 68 compounds revealed 8 hits representing 5 different chemical classes. One of the hits from the computational screen was found to inhibit DYRK1A with IC50 of 9.41 µM (Kd = 7.3 µM). Optimization of the hit compound and in vitro testing led to the identification of potent analogs with up to 100x improved binding. Synthesis, optimization and biological activity of the novel DYRK1A inhibitor will be presented.

Identification of a novel DYRK1A inhibitor lead from computational modeling of kinase inactive conformations

255th National Meeting (2018)

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