8v42
Structure of Human Vaccinia-related Kinase 1 (VRK1) Bound to ACH000400
Structural highlights
DiseaseVRK1_HUMAN Pontocerebellar hypoplasia type 1. The disease is caused by mutations affecting the gene represented in this entry. FunctionVRK1_HUMAN Serine/threonine kinase involved in Golgi disassembly during the cell cycle: following phosphorylation by PLK3 during mitosis, required to induce Golgi fragmentation. Acts by mediating phosphorylation of downstream target protein. Phosphorylates 'Thr-18' of p53/TP53 and may thereby prevent the interaction between p53/TP53 and MDM2. Phosphorylates casein and histone H3. Phosphorylates BANF1: disrupts its ability to bind DNA, reduces its binding to LEM domain-containing proteins and causes its relocalization from the nucleus to the cytoplasm. Phosphorylates ATF2 which activates its transcriptional activity.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedVaccinia-related kinase 1 (VRK1) and the delta and epsilon 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 CK1delta and CK1epsilon. We demonstrate that dihydropteridinones 35 and 36 mimic the cellular outcomes of VRK1 depletion. Complementary studies with existing CK1delta and CK1epsilon 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. Novel Dihydropteridinone Derivatives As Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 1delta/epsilon.,de Souza Gama FH, Dutra LA, Hawgood M, Dos Reis CV, Serafim RAM, Ferreira MA Jr, Teodoro BVM, Takarada JE, Santiago AS, Balourdas DI, Nilsson AS, Urien B, Almeida VM, Gileadi C, Ramos PZ, Salmazo A, Vasconcelos SNS, Cunha MR, Mueller S, Knapp S, Massirer KB, Elkins JM, Gileadi O, Mascarello A, Lemmens BBLG, Guimaraes CRW, Azevedo H, Counago RM J Med Chem. 2024 Jun 13;67(11):8609-8629. doi: 10.1021/acs.jmedchem.3c02250. Epub , 2024 May 23. PMID:38780468[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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