2. Academic Validation
  3. Novel Dihydropteridinone Derivatives As Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 1δ/ε

Novel Dihydropteridinone Derivatives As Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 1δ/ε

  • J Med Chem. 2024 Jun 13;67(11):8609-8629. doi: 10.1021/acs.jmedchem.3c02250.
Fernando H de Souza Gama 1,  Luiz A Dutra 2,  Michael Hawgood 3 4,  Caio Vinícius Dos Reis 2,  Ricardo A M Serafim 2,  Marcos A Ferreira Jr 1,  Bruno V M Teodoro 1,  Jéssica Emi Takarada 2,  André S Santiago 2,  Dimitrios-Ilias Balourdas 5 6,  Ann-Sofie Nilsson 3 4,  Bruno Urien 3 4,  Vitor M Almeida 2,  Carina Gileadi 2,  Priscila Z Ramos 2,  Anita Salmazo 2,  Stanley N S Vasconcelos 2,  Micael R Cunha 2,  Susanne Mueller 5 6,  Stefan Knapp 5 6,  Katlin B Massirer 2,  Jonathan M Elkins 2,  Opher Gileadi 2,  Alessandra Mascarello 1,  Bennie B L G Lemmens 3 4,  Cristiano R W Guimarães 1,  Hatylas Azevedo 1,  Rafael M Couñago 2
Affiliations

Affiliations

  • 1 Aché Laboratórios Farmacêuticos S.A., Guarulhos, São Paulo 07034-904, Brazil.
  • 2 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.
  • 3 Science for Life Laboratory, Sweden, Tomtebodavägen 23A, 17165 Solna, Sweden.
  • 4 Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden.
  • 5 Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Max-von-Laue-Str. 9, Frankfurt am Main 60438, Germany.
  • 6 Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Johann Wolfgang Goethe University, Max-von-Laue-Str. 15, Frankfurt am Main 60438, Germany.
PMID: 38780468 DOI: 10.1021/acs.jmedchem.3c02250
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 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.

Figures
Products
我们的 Cookie 政策

我们使用 Cookies 和类似技术以提高网站的性能和提升您的浏览体验，部分功能也使用 Cookies 帮助我们更好地理解您的需求，为您提供相关的服务。 如果您有任何关于我们如何处理您个人信息的疑问，请阅读我们的《隐私声明》。

嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z