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

Autor(es):Mostrar menos -

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]}

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: ACS Medicinal Chemistry Letters; v. 10, n. 9, p. 1266-1271, SEP 2019.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 18/03359-3 - Centro de Biologia Química de proteínas quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto
• Beneficiário: Fulvia Di Pillo
• Linha de fomento: Bolsas no Brasil - Programa Capacitação - Treinamento Técnico
• Processo FAPESP: 18/09475-5 - Novas abordagens para inibidores de proteínas quinases MRCKa, MRCKb e MRCKg
• Beneficiário: Stanley Nunes Siqueira Vasconcelos
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 13/50724-5 - Centro de Biologia Química de Proteínas Quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto
• Beneficiário: Paulo Arruda
• Linha de fomento: Auxílio à Pesquisa - Parceria para Inovação Tecnológica - PITE
• Processo FAPESP: 16/25320-6 - Planejamento e síntese de inibidores para proteínas quinases subexploradas relacionadas com RNA e epigenética
• Beneficiário: Ricardo Augusto Massarico Serafim
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado