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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Development of Pyridine-based Inhibitors for the Human Vaccinia-related Kinases 1 and 2

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Serafim, Ricardo A. M. [1, 2] ; de Souza Gama, Fernando H. [3] ; Dutra, Luiz A. [1, 2] ; dos Reis, Caio V. [1, 2] ; Vasconcelos, Stanley N. S. [1, 2] ; Santiago, Andre da Silva [1, 2] ; Takarada, Jessica E. [1, 2] ; Di Pillo, Fulvia [4] ; Azevedo, Hatylas [3] ; Mascarello, Alessandra [3] ; Elkins, Jonathan M. [5, 2] ; Massirer, Katlin B. [1, 2] ; Gileadi, Opher [5] ; Guimaraes, Cristiano R. W. [3] ; Counago, Rafael M. [1, 2]
Total Authors: 15
[1] Univ Estadual Campinas, UNICAMP, CBMEG, Ctr Quim Med CQMED, BR-13083875 Campinas, SP - Brazil
[2] Univ Estadual Campinas, Inst Biol, Dept Genet & Evolucao, Struct Genom Consortium, BR-13083886 Campinas, SP - Brazil
[3] Ache Lab Farmaceut SA, Guarulhos, SP - Brazil
[4] Univ Estadual Campinas, PhD Program Genet & Mol Biol PGBM, BR-13083886 Campinas, SP - Brazil
[5] Univ Oxford, Nuffield Dept Med, Struct Genom Consortium, Oxford OX3 7DQ - England
Total Affiliations: 5
Document type: Journal article
Source: ACS Medicinal Chemistry Letters; v. 10, n. 9, p. 1266-1271, SEP 2019.
Web of Science Citations: 0

Vaccinia-related kinases 1 and 2 (VRK1 and VRK2) are human Ser/Thr protein kinases associated with increased cell division and neurological disorders. Nevertheless, the cellular functions of these proteins are not fully understood. Despite their therapeutic potential, there are no potent and specific inhibitors available for VRK1 or VRK2. We report here the discovery and elaboration of an aminopyridine scaffold as a basis for VRK1 and VRK2 inhibitors. The most potent compound for VRK1 (26) displayed an IC50 value of 150 nM and was fairly selective in a panel of 48 human kinases (selectivity score S(50%) of 0.04). Differences in compound binding mode and substituent preferences between the two VRKs were identified by the structure-activity relationship combined with the crystallographic analysis of key compounds. We expect our results to serve as a starting point for the design of more specific and potent inhibitors against each of the two VRKs. (AU)

FAPESP's process: 18/03359-3 - Protein kinase chemical biology center: supporting drug development through open-access research
Grantee:Fulvia Di Pillo
Support Opportunities: Scholarships in Brazil - Technical Training Program - Technical Training
FAPESP's process: 18/09475-5 - New approaches to inhibitors for protein kinases MRCKa, MRCKb AND MRCKg
Grantee:Stanley Nunes Siqueira Vasconcelos
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 13/50724-5 - Protein Kinase Chemical Biology Center: supporting drug development through open-access research
Grantee:Paulo Arruda
Support Opportunities: Research Grants - Research Partnership for Technological Innovation - PITE
FAPESP's process: 16/25320-6 - Design and synthesis of inhibitors for understudied protein kinases related to RNA and epigenetics
Grantee:Ricardo Augusto Massarico Serafim
Support Opportunities: Scholarships in Brazil - Post-Doctoral