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Discovery of pyrazolo[3,4-d]pyrimidines as novel mitogen-activated protein kinase kinase 3 (MKK3) inhibitors

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Takarada, Jessica E. ; Cunha, Micael R. ; Almeida, Vitor M. ; Vasconcelos, Stanley N. S. ; Santiago, Andre S. ; Godoi, Paulo H. ; Salmazo, Anita ; Ramos, Priscila Z. ; Fala, Angela M. ; De Souza, Lucas R. ; Da Silva, Italo E. P. ; Bengtson, Mario H. ; Massirer, Katlin B. ; Counago, Rafael M.
Número total de Autores: 14
Tipo de documento: Artigo Científico
Fonte: Bioorganic & Medicinal Chemistry; v. 98, p. 13-pg., 2023-12-28.
Resumo

The dual-specificity protein kinase MKK3 has been implicated in tumor cell proliferation and survival, yet its precise role in cancer remains inconclusive. A critical step in elucidating the kinase's involvement in disease biology is the identification of potent, cell -permeable kinase inhibitors. Presently, MKK3 lacks a dedicated tool compound for these purposes, along with validated methods for the facile screening, identification, and optimization of inhibitors. In this study, we have developed a TR-FRET-based enzymatic assay for the detection of MKK3 activity in vitro and a BRET-based assay to assess ligand binding to this enzyme within intact human cells. These assays were instrumental in identifying hit compounds against MKK3 that share a common chemical scaffold, sourced from a library of bioactive kinase inhibitors. Initial hits were subsequently expanded through the synthesis of novel analogs. The resulting structure-activity relationship (SAR) was rationalized using molecular dynamics simulations against a homology model of MKK3. We expect our findings to expedite the development of novel, potent, selective, and bioactive inhibitors, thus facilitating investigations into MKK3 ' s role in various cancers. (AU)

Processo FAPESP: 21/04853-4 - Estudo do potencial terapêutico de novos moduladores do canal de cálcio lisossomal hTRPML1
Beneficiário:Micael Rodrigues Cunha
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Processo FAPESP: 14/50897-0 - INCT 2014: Centro de Química Medicinal de Acesso Aberto
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Modalidade de apoio: Auxílio à Pesquisa - Temático
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Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
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Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado