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From functional studies to searching for new inhibitors for cancer: exploring kinases that regulate the cell cycle of the human NEK family

Grant number: 17/03489-1
Support type:Research Projects - Thematic Grants
Duration: December 01, 2017 - November 30, 2022
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Jörg Kobarg
Grantee:Jörg Kobarg
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade Estadual de Campinas (UNICAMP). Campinas, SP, Brazil
Assoc. researchers:Carlos Frederico Martins Menck ; Daniel Fábio Kawano ; Daniel Martins-de-Souza ; Guido Lenz ; Hernandes Faustino de Carvalho ; Jonathan Mark Elkins ; Leonardo dos Reis Silveira ; Marcelo Bispo de Jesus ; Vadim Viviani
Associated scholarship(s):18/05350-3 - Study of the role of the interaction between mitofusin and Nek4 in the signaling between mitochondria and nucleus after cellular stress, BP.PD
15/06458-4 - Functional characterization of regulatory proteins involved in DNA repair, BP.PD

Abstract

Members of the family of NEK kinases (NIMA related kinases) were identified as important regulators of cell cycle checkpoints, especially at the G2 to M phase transition. Although they are among all kinases one of the least studied families, recent studies showed they can have crucial roles in mitosis, centrosome disjunction, and in the signaling of the DNA damage response. These characteristics along with the fact that several NEKs were found to be over-expressed in cancer, or were shown to present elevated mutation rates, suggest that they are interesting candidates both in the diagnostic as well as in the therapy of cancer. However, for most NEKs the physiological substrates have not been identified and nor are the functional consequences of the found point mutations known that occur in their genes in cancer cells. Therefore, the central aim of this project is to elucidate the functional roles of the NEKs in normal and tumoral cells. We will use the "Shokat" approach to generate kinase that are sensitive to ATP analogs to identify physiological substrates of the NEKs. Furthermore, we will generate mutations observed in Nek genes in cancer tissues to analyze functional consequences of these altered kinases in vitro and in vivo. Furthermore, we will characterize the protein expression of NEKs in normal and tumor tissues and 'high throughput screening' of inhibitors, based on coupled kinase/luciferase ATP consumption bioassay, previously developed in our group. In summary, our project envisions to study the physiological and pathophysiological roles of NEK 1, 3, 4, 5, 6, 7, 8 and 10. The studies will contribute to explore the potential of these cell cycle regulatory kinases as novel targets in the therapy of cancer and envision the discovery of novel anti-cancer inhibitors. (AU)

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