How to design potent and selective DYRK1B inhibitors? Molecular modeling study

  • Agnieszka Szamborska-Gbur
  • Ewelina Rutkowska
  • Agnieszka Dreas
  • Michael Frid
  • Maria Vilenchik
  • Mariusz Milik
  • Krzysztof Brzózka
  • Marcin KrólEmail author
Original Paper
Part of the following topical collections:
  1. 8th conference on Modeling & Design of Molecular Materials (MDMM 2018)


DYRK1B protein kinase is an emerging anticancer target due to its overexpression in a variety of cancers and its role in cancer chemoresistance through maintaining cancer cells in the G0 (quiescent) state. Consequently, there is a growing interest in the development of potent and selective DYRK1B inhibitors for anticancer therapy. One of the major off-targets is another protein kinase, GSK3β, which phosphorylates an important regulator of cell cycle progression on the same residue as DYRK1B and is involved in multiple signaling pathways. In the current work, we performed a detailed comparative structural analysis of DYRK1B and GSK3β ATP-binding sites and identified key regions responsible for selectivity. As the crystal structure of DYRK1B has never been reported, we built and optimized a homology model by comparative modeling and metadynamics simulations. Calculation of interaction energies between docked ligands in the ATP-binding sites of both kinases allowed us to pinpoint key residues responsible for potency and selectivity. Specifically, the role of the gatekeeper residues in DYRK1B and GSK3β is discussed in detail, and two other residues are identified as key to selectivity of DYRK1B inhibition versus GSK3β. The analysis presented in this work was used to support the design of potent and selective azaindole-quinoline-based DYRK1B inhibitors and can facilitate development of more selective inhibitors for DYRK kinases.


DYRK1B GSK3β Cancer cell quiescence Homology modeling Metadynamics simulations Kinase inhibitor selectivity 



This work was supported by the European Union from the European Regional Development Fund within the frame Operational Programme Innovative Economy (Grant No. UDA-POIG.01.04.00-12-048/11-00). Project title: New pharmacotherapy of neurodegenerative diseases: innovative kinase inhibitors.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Selvita S.A.KrakówPoland
  2. 2.Felicitex Therapeutics, Inc.NatickUSA

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