Functional and structural studies of protein kinases involved in cancer and neglected diseases: towards the development of new inhibitors

• Grant number: 10/51730-0
• Support Opportunities: Regular Research Grants
• Start date: January 01, 2011
• End date: December 31, 2012
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Jörg Kobarg
• Grantee: Jörg Kobarg
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil

Abstract

Protein kinases (PK) are regulatory proteins involved in practically all functional aspects of cells, most importantly in signal transduction. The human genome encodes more than 500 PK (2% of the genome), the most part of which can be affected by mutations than cause cancer or contribute to its progression. Based on this and the recent success of some PK inhibitors in the clinic (e.g. "Gleevec"), PK turned into one of the most attractive classes of target proteins for the development of new inhibitors. This project focuses on studies of the function-structure relationship of human PKs as well as of PKs from parasitic organisms, envisioning the development of inhibitors with potential for applications in pre-clinical and clinical trials. To this end we will invest in the development of in vitro and in vivo bioassays in "high throughput" and "high content" fashions, testing libraries of compounds of diverse origins (commercial, synthetic and natural products). The initial targets include all 11 members of the human NEK/NIMA family of proteins as well as selected members of this family from tropical disease causing parasites. Since Nek kinases are key regulators of the cell cycle, which expression or activity is found altered in certain cancer types, they represent excellent target candidates for the development of new inhibitors against cancer. Furthermore, human NEKs as well as NEKs from parasites such as Trypanosoma cruzi and Leishmania ssp., have so far not been explored for drug design and discovery. Recent studies suggest that Neks from protozoa are essential for the parasites viability and life cycle. Since they have low sequence similarity with the human Neks they represent attractive target candidates that should be explored for inhibitor discovery. This puts us in an ideal situation where we can explore inhibitor libraries in parallel bioassays in human and parasite cells. (AU)

Scientific publications

(9)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MORAIS, MARIANA A. B.; GIUSEPPE, PRISCILA O.; SOUZA, TATIANA A. C. B.; CASTRO, HELENA; HONORATO, RODRIGO V.; OLIVEIRA, PAULO S. L.; NETTO, LUIS E. S.; TOMAS, ANA M.; MURAKAMI, MARIO T.. Calcium and magnesium ions modulate the oligomeric state and function of mitochondrial 2-Cys peroxiredoxins in Leishmania parasites. Journal of Biological Chemistry, v. 292, n. 17, p. 7023-7039, APR 28 2017. (15/05851-4, 11/10248-4, 10/51730-0, 12/24134-3)

VIEIRA, PLINIO SALMAZO; DE GIUSEPPE, PRISCILA OLIVEIRA; CAVALCANTE DE OLIVEIRA, ARTHUR HENRIQUE; MURAKAMI, MARIO TYAGO. The role of the C-terminus and Kpn loop in the quaternary structure stability of nucleoside diphosphate kinase from Leishmania parasites. Journal of Structural Biology, v. 192, n. 3, p. 336-341, DEC 2015. (11/20569-2, 10/03761-4, 07/06755-2, 11/24178-8, 10/51730-0)

MORAIS, MARIANA A. B.; GIUSEPPE, PRISCILA O.; SOUZA, TATIANA A. C. B.; ALEGRIA, THIAGO G. P.; OLIVEIRA, MARCOS A.; NETTO, LUIS E. S.; MURAKAMI, MARIO T.. How pH Modulates the Dimer-Decamer Interconversion of 2-Cys Peroxiredoxins from the Prx1 Subfamily. Journal of Biological Chemistry, v. 290, n. 13, p. 8582-8590, MAR 27 2015. (11/10248-4, 10/51730-0, 12/24134-3)

MELO-HANCHUK, TALITA D.; SLEPICKA, PRISCILA FERREIRA; MEIRELLES, GABRIELA VAZ; BASEI, FERNANDA LUISA; LOVATO, DIOGO VENTURA; GRANATO, DANIELA CAMPOS; PAULETTI, BIANCA ALVES; DOMINGUES, ROMENIA RAMOS; PAES LEME, ADRIANA FRANCO; PELEGRINI, ALESSANDRA LUIZA; et al. NEK1 kinase domain structure and its dynamic protein interactome after exposure to Cisplatin. SCIENTIFIC REPORTS, v. 7, JUL 14 2017. (10/51730-0)

BASEI, FERNANDA LUISA; MEIRELLES, GABRIELA VAZ; RIGHETTO, GERMANNA LIMA; DOS SANTOS MIGUELETI, DEIVID LUCAS; COSTA SMETANA, JULIANA HELENA; KOBARG, JOERG. New interaction partners for Nek4.1 and Nek4.2 isoforms: from the DNA damage response to RNA splicing. PROTEOME SCIENCE, v. 13, FEB 26 2015. (10/51730-0)

MELO HANCHUK, TALITA D.; PAPA, PRISCILA FERREIRA; LA GUARDIA, PAOLO G.; VERCESI, ANIBAL E.; KOBARG, JOERG. Nek5 interacts with mitochondrial proteins and interferes negatively in mitochondrial mediated cell death and respiration. CELLULAR SIGNALLING, v. 27, n. 6, p. 1168-1177, JUN 2015. (10/51730-0, 10/16831-0)

VIEIRA, PLINIO SALMAZO; CAMPOS BRASIL SOUZA, TATIANA DE ARRUDA; HONORATO, RODRIGO VARGAS; ZANPHORLIN, LETICIA MARIA; SEVERIANO, KELVEN ULISSES; ROCCO, SILVANA APARECIDA; CAVALCANTE DE OLIVEIRA, ARTHUR HENRIQUE; CORDEIRO, ARTUR TORRES; LOPES OLIVEIRA, PAULO SERGIO; DE GIUSEPPE, PRISCILA OLIVEIRA; et al. Pyrrole-indolinone SU11652 targets the nucleoside diphosphate kinase from Leishmania parasites. Biochemical and Biophysical Research Communications, v. 488, n. 3, p. 461-465, JUL 1 2017. (11/20569-2, 10/03761-4, 07/06755-2, 11/24178-8, 10/51730-0)

MELO-HANCHUK, TALITA DINIZ; SLEPICKA, PRISCILA FERREIRA; PELEGRINI, ALESSANDRA LUIZA; MARTINS MENCK, CARLOS FREDERICO; KOBARG, JORG. NEK5 interacts with topoisomerase II beta and is involved in the DNA damage response induced by etoposide. Journal of Cellular Biochemistry, v. 120, n. 10, p. 16853-16866, OCT 2019. (14/15982-6, 17/03489-1, 10/51730-0, 15/06458-4, 10/16831-0, 10/15262-2)

DE SOUZA, EDMARCIA ELISA; HEHNLY, HEIDI; PEREZ, ARINA MARINA; MEIRELLES, GABRIELA VAZ; COSTA SMETANA, JULIANA HELENA; DOXSEY, STEPHEN; KOBARG, JOERG. Human Nek7-interactor RGS2 is required for mitotic spindle organization. CELL CYCLE, v. 14, n. 4, p. 656-667, FEB 15 2015. (10/51730-0)