{"article_type":"original","external_id":{"pmid":["38780468"]},"volume":67,"abstract":[{"lang":"eng","text":"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."}],"date_published":"2024-05-23T00:00:00Z","title":"Novel dihydropteridinone derivatives as potent inhibitors of the understudied human kinases vaccinia-related kinase 1 and casein kinase 1δ/ε","publisher":"American Chemical Society","_id":"18945","publication":"Journal of Medicinal Chemistry","doi":"10.1021/acs.jmedchem.3c02250","quality_controlled":"1","day":"23","year":"2024","citation":{"ama":"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. <i>Journal of Medicinal Chemistry</i>. 2024;67(11):8609-8629. doi:<a href=\"https://doi.org/10.1021/acs.jmedchem.3c02250\">10.1021/acs.jmedchem.3c02250</a>","short":"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.","ista":"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.","ieee":"F. H. de Souza Gama <i>et al.</i>, “Novel dihydropteridinone derivatives as potent inhibitors of the understudied human kinases vaccinia-related kinase 1 and casein kinase 1δ/ε,” <i>Journal of Medicinal Chemistry</i>, vol. 67, no. 11. American Chemical Society, pp. 8609–8629, 2024.","chicago":"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.” <i>Journal of Medicinal Chemistry</i>. American Chemical Society, 2024. <a href=\"https://doi.org/10.1021/acs.jmedchem.3c02250\">https://doi.org/10.1021/acs.jmedchem.3c02250</a>.","apa":"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. <i>Journal of Medicinal Chemistry</i>. American Chemical Society. <a href=\"https://doi.org/10.1021/acs.jmedchem.3c02250\">https://doi.org/10.1021/acs.jmedchem.3c02250</a>","mla":"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.” <i>Journal of Medicinal Chemistry</i>, 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>."},"type":"journal_article","pmid":1,"month":"05","intvolume":"        67","language":[{"iso":"eng"}],"status":"public","date_updated":"2025-01-29T09:19:15Z","date_created":"2025-01-29T09:14:19Z","oa_version":"None","OA_type":"closed access","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","acknowledgement":"R.M.C. and K.B.M. are grateful for support by FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo) (grants 2013/50724–5 and 2014/50897–0), Embrapii (Empresa Brasileira de Pesquisa e Inovação Industrial), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) (grant 465651/2014–3) and Aché Laboratórios Farmacêuticos. R.M.C. and O.G. are also grateful for support by the Structural Genomics Consortium, a registered charity (1097737) that receives funds from AbbVie, Bayer AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genentech, Genome Canada through the Ontario Genomics Institute (OGI-196), EU/EFPIA/OICR/McGill/KTH/Diamond, Innovative Medicines Initiative 2 Joint Undertaking (EUbOPEN Grant 875510), Janssen, Merck KGaA, Merck & Co., Pfizer, Takeda, and Wellcome. B.L. and M.H. are grateful for support from the Swedish Research Council, Swedish Cancer Society, Karolinska Institutet and The Mark Foundation for Cancer Research. R.A.M.S. (2016/25320–6 and 2018/23322–7), A.S.S. (2019/14275–8), S.N.S.V (2018/09475–5), V.M.A. (2022/00743–2) and M.R.C. (2021/04853–4) were recipients of fellowships from the Fundação de Amparo à Pesquisa do Estado de São Paulo, FAPESP. C.V.R. (88887.146077/2017–00), J.E.T. (88887.373547/2019–00) and P.Z.R (88887.136432/2017–00) were the recipient of fellowships from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, CAPES.\r\nWe thank all members of CQMED-UNICAMP for their help and support. We thank the staff of the Life Sciences Core Facility (LaCTAD) at UNICAMP for the Genomics and Mass Spectrometry analysis. We thank the NMR facility at UNICAMP Chemistry Institute for its assistance. We thank the staff at the Northeastern Collaborative Access Team beamlines, which are funded by the National Institute of General Medical Sciences from the National Institutes of Health (P41 GM103403). The Pilatus 6M detector on the 24-ID-C beamline is funded by a NIH-ORIP HEI grant (S10 RR029205). This research used resources of the Advanced Photon Source; a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. We thank Diamond Light Source for access to beamline I24. The authors thank Tammy Havener (SGC-UNC), Abid Hussain Sayyid (KI), and Yiqiu Yang (KI) for valuable discussions and technical support.","department":[{"_id":"CaBe"}],"publication_status":"published","publication_identifier":{"eissn":["1520-4804"],"issn":["0022-2623"]},"author":[{"full_name":"de Souza Gama, Fernando H.","last_name":"de Souza Gama","first_name":"Fernando H."},{"first_name":"Luiz A.","full_name":"Dutra, Luiz A.","last_name":"Dutra"},{"last_name":"Hawgood","full_name":"Hawgood, Michael","first_name":"Michael"},{"last_name":"dos Reis","full_name":"dos Reis, Caio Vinícius","first_name":"Caio Vinícius"},{"first_name":"Ricardo A. M.","last_name":"Serafim","full_name":"Serafim, Ricardo A. M."},{"full_name":"Ferreira, Marcos A.","last_name":"Ferreira","first_name":"Marcos A."},{"first_name":"Bruno V. M.","full_name":"Teodoro, Bruno V. M.","last_name":"Teodoro"},{"first_name":"Jéssica Emi","full_name":"Takarada, Jéssica Emi","last_name":"Takarada"},{"last_name":"Santiago","full_name":"Santiago, André S.","first_name":"André S."},{"first_name":"Dimitrios-Ilias","full_name":"Balourdas, Dimitrios-Ilias","last_name":"Balourdas"},{"full_name":"Nilsson, Ann-Sofie","last_name":"Nilsson","first_name":"Ann-Sofie"},{"full_name":"Urien, Bruno","last_name":"Urien","first_name":"Bruno"},{"first_name":"Vitor M.","full_name":"Almeida, Vitor M.","last_name":"Almeida"},{"first_name":"Carina","full_name":"Gileadi, Carina","last_name":"Gileadi"},{"full_name":"Ramos, Priscila Z.","last_name":"Ramos","first_name":"Priscila Z."},{"id":"41F1F098-F248-11E8-B48F-1D18A9856A87","first_name":"Anita P","last_name":"Testa Salmazo","full_name":"Testa Salmazo, Anita P"},{"first_name":"Stanley N. S.","last_name":"Vasconcelos","full_name":"Vasconcelos, Stanley N. S."},{"first_name":"Micael R.","last_name":"Cunha","full_name":"Cunha, Micael R."},{"last_name":"Mueller","full_name":"Mueller, Susanne","first_name":"Susanne"},{"full_name":"Knapp, Stefan","last_name":"Knapp","first_name":"Stefan"},{"first_name":"Katlin B.","full_name":"Massirer, Katlin B.","last_name":"Massirer"},{"last_name":"Elkins","full_name":"Elkins, Jonathan M.","first_name":"Jonathan M."},{"last_name":"Gileadi","full_name":"Gileadi, Opher","first_name":"Opher"},{"full_name":"Mascarello, Alessandra","last_name":"Mascarello","first_name":"Alessandra"},{"first_name":"Bennie B. L. G.","full_name":"Lemmens, Bennie B. L. G.","last_name":"Lemmens"},{"first_name":"Cristiano R. W.","full_name":"Guimarães, Cristiano R. W.","last_name":"Guimarães"},{"last_name":"Azevedo","full_name":"Azevedo, Hatylas","first_name":"Hatylas"},{"last_name":"Couñago","full_name":"Couñago, Rafael M.","first_name":"Rafael M."}],"article_processing_charge":"No","page":"8609-8629","issue":"11","scopus_import":"1"}