8V42

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

8V42 の概要

• エントリーDOI: 10.2210/pdb8v42/pdb
• 分子名称: 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)
• 機能のキーワード: protein kinase, inhibitor, co-crystal, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 165895.62

構造登録者

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

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.3 Å)