2. Academic Validation
  3. Novel Dihydropteridinone Derivatives As Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 1δ/ε

Novel Dihydropteridinone Derivatives As Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 1δ/ε

  • J Med Chem. 2024 Jun 13;67(11):8609-8629. doi: 10.1021/acs.jmedchem.3c02250.
Fernando H de Souza Gama 1,  Luiz A Dutra 2,  Michael Hawgood 3 4,  Caio Vinícius Dos Reis 2,  Ricardo A M Serafim 2,  Marcos A Ferreira Jr 1,  Bruno V M Teodoro 1,  Jéssica Emi Takarada 2,  André S Santiago 2,  Dimitrios-Ilias Balourdas 5 6,  Ann-Sofie Nilsson 3 4,  Bruno Urien 3 4,  Vitor M Almeida 2,  Carina Gileadi 2,  Priscila Z Ramos 2,  Anita Salmazo 2,  Stanley N S Vasconcelos 2,  Micael R Cunha 2,  Susanne Mueller 5 6,  Stefan Knapp 5 6,  Katlin B Massirer 2,  Jonathan M Elkins 2,  Opher Gileadi 2,  Alessandra Mascarello 1,  Bennie B L G Lemmens 3 4,  Cristiano R W Guimarães 1,  Hatylas Azevedo 1,  Rafael M Couñago 2
Affiliations

Affiliations

  • 1 Aché Laboratórios Farmacêuticos S.A., Guarulhos, São Paulo 07034-904, Brazil.
  • 2 Centro de Química Medicinal, Centro de Biologia Molecular e Engenharia Genética, Universidade Estadual de Campinas, Av. Dr. André Tosello 550, 13083-886 Campinas, São Paulo Brazil.
  • 3 Science for Life Laboratory, Sweden, Tomtebodavägen 23A, 17165 Solna, Sweden.
  • 4 Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden.
  • 5 Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Max-von-Laue-Str. 9, Frankfurt am Main 60438, Germany.
  • 6 Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Johann Wolfgang Goethe University, Max-von-Laue-Str. 15, Frankfurt am Main 60438, Germany.
PMID: 38780468 DOI: 10.1021/acs.jmedchem.3c02250
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.

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