@article{18945,
  abstract     = {Vaccinia-related kinase 1 (VRK1) and the δ and ε isoforms of casein kinase 1 (CK1) are linked to various disease-relevant pathways. However, the lack of tool compounds for these kinases has significantly hampered our understanding of their cellular functions and therapeutic potential. Here, we describe the structure-based development of potent inhibitors of VRK1, a kinase highly expressed in various tumor types and crucial for cell proliferation and genome integrity. Kinome-wide profiling revealed that our compounds also inhibit CK1δ and CK1ε. We demonstrate that dihydropteridinones 35 and 36 mimic the cellular outcomes of VRK1 depletion. Complementary studies with existing CK1δ and CK1ε inhibitors suggest that these kinases may play overlapping roles in cell proliferation and genome instability. Together, our findings highlight the potential of VRK1 inhibition in treating p53-deficient tumors and possibly enhancing the efficacy of existing cancer therapies that target DNA stability or cell division.},
  author       = {de Souza Gama, Fernando H. and Dutra, Luiz A. and Hawgood, Michael and dos Reis, Caio Vinícius and Serafim, Ricardo A. M. and Ferreira, Marcos A. and Teodoro, Bruno V. M. and Takarada, Jéssica Emi and Santiago, André S. and Balourdas, Dimitrios-Ilias and Nilsson, Ann-Sofie and Urien, Bruno and Almeida, Vitor M. and Gileadi, Carina and Ramos, Priscila Z. and Testa Salmazo, Anita P and Vasconcelos, Stanley N. S. and Cunha, Micael R. and Mueller, Susanne and Knapp, Stefan and Massirer, Katlin B. and Elkins, Jonathan M. and Gileadi, Opher and Mascarello, Alessandra and Lemmens, Bennie B. L. G. and Guimarães, Cristiano R. W. and Azevedo, Hatylas and Couñago, Rafael M.},
  issn         = {1520-4804},
  journal      = {Journal of Medicinal Chemistry},
  number       = {11},
  pages        = {8609--8629},
  publisher    = {American Chemical Society},
  title        = {{Novel dihydropteridinone derivatives as potent inhibitors of the understudied human kinases vaccinia-related kinase 1 and casein kinase 1δ/ε}},
  doi          = {10.1021/acs.jmedchem.3c02250},
  volume       = {67},
  year         = {2024},
}