دورية أكاديمية
Novel Dihydropteridinone Derivatives As Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 1δ/ε.
| العنوان: | Novel Dihydropteridinone Derivatives As Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 1δ/ε. |
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| المؤلفون: | de Souza Gama FH; Aché Laboratórios Farmacêuticos S.A., Guarulhos, São Paulo 07034-904, Brazil., Dutra LA; 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., Hawgood M; Science for Life Laboratory, Sweden, Tomtebodavägen 23A, 17165 Solna, Sweden.; Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden., Dos Reis CV; 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., Serafim RAM; 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., Ferreira MA Jr; Aché Laboratórios Farmacêuticos S.A., Guarulhos, São Paulo 07034-904, Brazil., Teodoro BVM; Aché Laboratórios Farmacêuticos S.A., Guarulhos, São Paulo 07034-904, Brazil., Takarada JE; 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., Santiago AS; 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., Balourdas DI; Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Max-von-Laue-Str. 9, Frankfurt am Main 60438, Germany.; Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Johann Wolfgang Goethe University, Max-von-Laue-Str. 15, Frankfurt am Main 60438, Germany., Nilsson AS; Science for Life Laboratory, Sweden, Tomtebodavägen 23A, 17165 Solna, Sweden.; Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden., Urien B; Science for Life Laboratory, Sweden, Tomtebodavägen 23A, 17165 Solna, Sweden.; Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden., Almeida VM; 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., Gileadi C; 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., Ramos PZ; 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., Salmazo A; 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., Vasconcelos SNS; 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., Cunha MR; 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., Mueller S; Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Max-von-Laue-Str. 9, Frankfurt am Main 60438, Germany.; Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Johann Wolfgang Goethe University, Max-von-Laue-Str. 15, Frankfurt am Main 60438, Germany., Knapp S; Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Max-von-Laue-Str. 9, Frankfurt am Main 60438, Germany.; Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Johann Wolfgang Goethe University, Max-von-Laue-Str. 15, Frankfurt am Main 60438, Germany., Massirer KB; 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., Elkins JM; 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., Gileadi O; 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., Mascarello A; Aché Laboratórios Farmacêuticos S.A., Guarulhos, São Paulo 07034-904, Brazil., Lemmens BBLG; Science for Life Laboratory, Sweden, Tomtebodavägen 23A, 17165 Solna, Sweden.; Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden., Guimarães CRW; Aché Laboratórios Farmacêuticos S.A., Guarulhos, São Paulo 07034-904, Brazil., Azevedo H; Aché Laboratórios Farmacêuticos S.A., Guarulhos, São Paulo 07034-904, Brazil., Couñago RM; 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. |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2024 Jun 13; Vol. 67 (11), pp. 8609-8629. Date of Electronic Publication: 2024 May 23. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| مواضيع طبية MeSH: | Protein Kinase Inhibitors*/pharmacology , Protein Kinase Inhibitors*/chemistry , Protein Kinase Inhibitors*/chemical synthesis , Protein Serine-Threonine Kinases*/antagonists & inhibitors , Protein Serine-Threonine Kinases*/metabolism , Pteridines*/pharmacology , Pteridines*/chemistry , Pteridines*/chemical synthesis, Humans ; Intracellular Signaling Peptides and Proteins/antagonists & inhibitors ; Intracellular Signaling Peptides and Proteins/metabolism ; Cell Proliferation/drug effects ; Structure-Activity Relationship ; Casein Kinase Idelta/antagonists & inhibitors ; Casein Kinase Idelta/metabolism ; Casein Kinase 1 epsilon/antagonists & inhibitors ; Casein Kinase 1 epsilon/metabolism ; Cell Line, Tumor |
| مستخلص: | 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. |
| المشرفين على المادة: | EC 2.7.11.1 (VRK1 protein, human) 0 (Protein Kinase Inhibitors) EC 2.7.11.1 (Protein Serine-Threonine Kinases) 0 (Pteridines) 0 (Intracellular Signaling Peptides and Proteins) EC 2.7.11.1 (Casein Kinase Idelta) EC 2.7.11.1 (Casein Kinase 1 epsilon) |
| تواريخ الأحداث: | Date Created: 20240523 Date Completed: 20240613 Latest Revision: 20240613 |
| رمز التحديث: | 20240613 |
| DOI: | 10.1021/acs.jmedchem.3c02250 |
| PMID: | 38780468 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.3c02250 |