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Type: Artigo de periódico
Title: Kinase Inhibitor Profile For Human Nek1, Nek6, And Nek7 And Analysis Of The Structural Basis For Inhibitor Specificity.
Author: Moraes, Eduardo Cruz
Meirelles, Gabriela Vaz
Honorato, Rodrigo Vargas
de Souza, Tatiana de Arruda Campos Brasil
de Souza, Edmarcia Elisa
Murakami, Mario Tyago
de Oliveira, Paulo Sergio Lopes
Kobarg, Jörg
Abstract: Human Neks are a conserved protein kinase family related to cell cycle progression and cell division and are considered potential drug targets for the treatment of cancer and other pathologies. We screened the activation loop mutant kinases hNek1 and hNek2, wild-type hNek7, and five hNek6 variants in different activation/phosphorylation statesand compared them against 85 compounds using thermal shift denaturation. We identified three compounds with significant Tm shifts: JNK Inhibitor II for hNek1(Δ262-1258)-(T162A), Isogranulatimide for hNek6(S206A), andGSK-3 Inhibitor XIII for hNek7wt. Each one of these compounds was also validated by reducing the kinases activity by at least 25%. The binding sites for these compounds were identified by in silico docking at the ATP-binding site of the respective hNeks. Potential inhibitors were first screened by thermal shift assays, had their efficiency tested by a kinase assay, and were finally analyzed by molecular docking. Our findings corroborate the idea of ATP-competitive inhibition for hNek1 and hNek6 and suggest a novel non-competitive inhibition for hNek7 in regard to GSK-3 Inhibitor XIII. Our results demonstrate that our approach is useful for finding promising general and specific hNekscandidate inhibitors, which may also function as scaffolds to design more potent and selective inhibitors.
Citation: Molecules (basel, Switzerland). v. 20, n. 1, p. 1176-91, 2015.
Rights: aberto
Identifier DOI: 10.3390/molecules20011176
Date Issue: 2015
Appears in Collections:Unicamp - Artigos e Outros Documentos

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