8V42

Structure of Human Vaccinia-related Kinase 1 (VRK1) Bound to ACH000400

Summary for 8V42

• Entry DOI: 10.2210/pdb8v42/pdb
• Descriptor: Serine/threonine-protein kinase VRK1, DI(HYDROXYETHYL)ETHER, (7S)-2-(3,5-difluoro-4-hydroxyanilino)-7-methyl-5-[(1,2-oxazol-5-yl)methyl]-8-(prop-2-yn-1-yl)-7,8-dihydropteridin-6(5H)-one, ... (5 entities in total)
• Functional Keywords: protein kinase, inhibitor, co-crystal, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 165895.62

Authors

Counago, R.M.,de Souza, G.P.,Azevedo, A.,Guimaraes, C.,Mascarello, A.,Gama, F.,Ferreira, M.,Arruda, P. (deposition date: 2023-11-28, release date: 2024-09-04)

Primary citation

de Souza Gama, F.H.,Dutra, L.A.,Hawgood, M.,Dos Reis, C.V.,Serafim, R.A.M.,Ferreira Jr., M.A.,Teodoro, B.V.M.,Takarada, J.E.,Santiago, A.S.,Balourdas, D.I.,Nilsson, A.S.,Urien, B.,Almeida, V.M.,Gileadi, C.,Ramos, P.Z.,Salmazo, A.,Vasconcelos, S.N.S.,Cunha, M.R.,Mueller, S.,Knapp, S.,Massirer, K.B.,Elkins, J.M.,Gileadi, O.,Mascarello, A.,Lemmens, B.B.L.G.,Guimaraes, C.R.W.,Azevedo, H.,Counago, R.M.
Novel Dihydropteridinone Derivatives As Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 1 delta / epsilon.
J.Med.Chem., 67:8609-8629, 2024

PubMed 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 and 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.

PubMed: 38780468
DOI: 10.1021/acs.jmedchem.3c02250

Experimental method

X-RAY DIFFRACTION (2.3 Å)