In Depth Analysis of Kinase Cross Screening Data to Identify CAMKK2 Inhibitory Scaffolds

Autor(es):Mostrar menos -

O'Byrne, Sean N. ^[1] ; Scott, John W. ^{[2, 3, 4, 5]} ; Pilotte, Joseph R. ^[1] ; Santiago, Andre da S. ^{[6, 7]} ; Langendorf, Christopher G. ^{[3, 4]} ; Oakhill, Jonathan S. ^{[2, 3, 4]} ; Eduful, Benjamin J. ^[1] ; Counago, Rafael M. ^{[6, 7]} ; Wells, Carrow I. ^[1] ; Zuercher, William J. ^[1] ; Willson, Timothy M. ^[1] ; Drewry, David H. ^[1]

Afiliação do(s) autor(es)

^[1] Univ North Carolina Chapel Hill, Struct Genom Consortium, UNC Eshelman Sch Pharm, Chapel Hill, NC 27599 - USA

^[2] Australian Catholic Univ, Mary MacKillop Inst Hlth Res, 215 Spring St, Melbourne, Vic 3000 - Australia

^[3] Univ Melbourne, St Vincents Inst, 41 Victoria Parade, Fitzroy, Vic 3065 - Australia

^[4] Univ Melbourne, Dept Med, 41 Victoria Parade, Fitzroy, Vic 3065 - Australia

^[5] Florey Inst Neurosci & Mental Hlth, 30 Royal Parade, Parkville, Vic 3052 - Australia

^[6] Univ Estadual Campinas, Inst Biol, Dept Genet & Evolucao, Struct Genom Consortium, BR-13083886 Campinas, SP - Brazil

^[7] Univ Estadual Campinas UNICAMP, Ctr Quim Med CQMED, CBMEG, BR-13083875 Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Molecules; v. 25, n. 2 JAN 2 2020.
• Citações Web of Science: 1

Resumo

The calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) activates CAMK1, CAMK4, AMPK, and AKT, leading to numerous physiological responses. The deregulation of CAMKK2 is linked to several diseases, suggesting the utility of CAMKK2 inhibitors for oncological, metabolic and inflammatory indications. In this work, we demonstrate that STO-609, frequently described as a selective inhibitor for CAMKK2, potently inhibits a significant number of other kinases. Through an analysis of literature and public databases, we have identified other potent CAMKK2 inhibitors and verified their activities in differential scanning fluorimetry and enzyme inhibition assays. These inhibitors are potential starting points for the development of selective CAMKK2 inhibitors and will lead to tools that delineate the roles of this kinase in disease biology. (AU)

• 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
• Modalidade de apoio: Auxílio à Pesquisa - Parceria para Inovação Tecnológica - PITE
• Processo FAPESP: 19/14275-8 - Análise estrutural das proteínas quinases PRPF4 and DYRK1B pertencentes à família CMGC e identificação de pequenos compostos inibidores
• Beneficiário: André da Silva Santiago
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 14/50897-0 - INCT 2014: Centro de Química Medicinal de Acesso Aberto
• Beneficiário: Katlin Brauer Massirer
• Modalidade de apoio: Auxílio à Pesquisa - Temático