Novel dihydropteridinone derivatives as potent inhibitors of the understudied human kinases vaccinia-related kinase 1 and casein kinase 1δ/ε

article Novel dihydropteridinone derivatives as potent inhibitors of the understudied human kinases vaccinia-related kinase 1 and casein kinase 1δ/ε published yes Fernando H. de Souza Gama author Luiz A. Dutra author Michael Hawgood author Caio Vinícius dos Reis author Ricardo A. M. Serafim author Marcos A. Ferreira author Bruno V. M. Teodoro author Jéssica Emi Takarada author André S. Santiago author Dimitrios-Ilias Balourdas author Ann-Sofie Nilsson author Bruno Urien author Vitor M. Almeida author Carina Gileadi author Priscila Z. Ramos author Anita P Testa Salmazo author 41F1F098-F248-11E8-B48F-1D18A9856A87 Stanley N. S. Vasconcelos author Micael R. Cunha author Susanne Mueller author Stefan Knapp author Katlin B. Massirer author Jonathan M. Elkins author Opher Gileadi author Alessandra Mascarello author Bennie B. L. G. Lemmens author Cristiano R. W. Guimarães author Hatylas Azevedo author Rafael M. Couñago author CaBe department 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. American Chemical Society2024 eng Journal of Medicinal Chemistry 0022-2623 1520-4804 3878046810.1021/acs.jmedchem.3c02250 67118609-8629 de Souza Gama, Fernando H., et al. “Novel Dihydropteridinone Derivatives as Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 1δ/ε.” Journal of Medicinal Chemistry, vol. 67, no. 11, American Chemical Society, 2024, pp. 8609–29, doi:<a href="https://doi.org/10.1021/acs.jmedchem.3c02250">10.1021/acs.jmedchem.3c02250</a>. F.H. de Souza Gama, L.A. Dutra, M. Hawgood, C.V. dos Reis, R.A.M. Serafim, M.A. Ferreira, B.V.M. Teodoro, J.E. Takarada, A.S. Santiago, D.-I. Balourdas, A.-S. Nilsson, B. Urien, V.M. Almeida, C. Gileadi, P.Z. Ramos, A.P. Testa Salmazo, S.N.S. Vasconcelos, M.R. Cunha, S. Mueller, S. Knapp, K.B. Massirer, J.M. Elkins, O. Gileadi, A. Mascarello, B.B.L.G. Lemmens, C.R.W. Guimarães, H. Azevedo, R.M. Couñago, Journal of Medicinal Chemistry 67 (2024) 8609–8629. Souza Gama, Fernando H. de, Luiz A. Dutra, Michael Hawgood, Caio Vinícius dos Reis, Ricardo A. M. Serafim, Marcos A. Ferreira, Bruno V. M. Teodoro, et al. “Novel Dihydropteridinone Derivatives as Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 1δ/ε.” Journal of Medicinal Chemistry. American Chemical Society, 2024. <a href="https://doi.org/10.1021/acs.jmedchem.3c02250">https://doi.org/10.1021/acs.jmedchem.3c02250</a>. de Souza Gama, F. H., Dutra, L. A., Hawgood, M., dos Reis, C. V., Serafim, R. A. M., Ferreira, M. A., … Couñago, R. M. (2024). Novel dihydropteridinone derivatives as potent inhibitors of the understudied human kinases vaccinia-related kinase 1 and casein kinase 1δ/ε. Journal of Medicinal Chemistry. American Chemical Society. <a href="https://doi.org/10.1021/acs.jmedchem.3c02250">https://doi.org/10.1021/acs.jmedchem.3c02250</a> de Souza Gama FH, Dutra LA, Hawgood M, dos Reis CV, Serafim RAM, Ferreira MA, Teodoro BVM, Takarada JE, Santiago AS, Balourdas D-I, Nilsson A-S, Urien B, Almeida VM, Gileadi C, Ramos PZ, Testa Salmazo AP, Vasconcelos SNS, Cunha MR, Mueller S, Knapp S, Massirer KB, Elkins JM, Gileadi O, Mascarello A, Lemmens BBLG, Guimarães CRW, Azevedo H, Couñago RM. 2024. Novel dihydropteridinone derivatives as potent inhibitors of the understudied human kinases vaccinia-related kinase 1 and casein kinase 1δ/ε. Journal of Medicinal Chemistry. 67(11), 8609–8629. F. H. de Souza Gama et al., “Novel dihydropteridinone derivatives as potent inhibitors of the understudied human kinases vaccinia-related kinase 1 and casein kinase 1δ/ε,” Journal of Medicinal Chemistry, vol. 67, no. 11. American Chemical Society, pp. 8609–8629, 2024. de Souza Gama FH, Dutra LA, Hawgood M, et al. Novel dihydropteridinone derivatives as potent inhibitors of the understudied human kinases vaccinia-related kinase 1 and casein kinase 1δ/ε. Journal of Medicinal Chemistry. 2024;67(11):8609-8629. doi:<a href="https://doi.org/10.1021/acs.jmedchem.3c02250">10.1021/acs.jmedchem.3c02250</a> 189452025-01-29T09:14:19Z2025-01-29T09:19:15Z