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New approaches to inhibitors for protein kinases MRCKa, MRCKb AND MRCKg

Grant number: 18/09475-5
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): October 01, 2018
Effective date (End): September 30, 2021
Field of knowledge:Physical Sciences and Mathematics - Chemistry
Principal Investigator:Katlin Brauer Massirer
Grantee:Stanley Nunes Siqueira Vasconcelos
Host Institution: Centro de Biologia Molecular e Engenharia Genética (CBMEG). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil


Protein kinases are the enzyme family involved in the control and modulation of a wide range of biological process. Their catalytic activity comprises the transfer of a phosphate group from adenosine triphosphate (ATP) to protein substrates containing tyrosine, serine and/or threonine amino acid residues. In order to understand the function of each of the ~500 kinases and their effect on substrates, researchers have used mostly genetics approaches of kinase inhibition. One of the understudied class of kinases are the MRCKs (myotonic dystrophy kinase-related CDC42-binding kinases), which were related to the process of cytoskeleton actomyosin regulation in cancer invasion and cellular metastasis. In this project we are going to use a medicinal chemistry approach of chemical inhibition to investigate the therapeutic significance of unexplored kinases MRCKa, MRCKb, MRCKg (DMPK2) kinases. We aim to designing and synthesizing molecules that can interact potently and selectively with MRCKs in order to understand their biological role. During the last six months we have initiated protein binding screens for kinase inhibitor candidates for MRCKs and we have selected potential chemical candidates. Based on this screening we hypothesize that pteridine and pyrazolo[3,4-d]pyrimidine scaffolds can lead to potent and selective MRCK inhibitors. The synthesized compounds will be subjected to structure-activity relationship studies, protein-ligand co-crystallization experiments in order to obtain the crystal structure and biological assays in vitro and in cell lines. After lead-compound identification/optimization, the selectivity of the best compounds will be measured against a panel of protein kinase-domains covering different branches of the kinome. The project will be developed in the Structural Genomics Consortium (SGC-FAPESP@Unicamp) laboratories, and the chemical synthesis will be done in close interaction with the structural biology team, to help accelerate the kinase inhibitor discovery. As outcome of the project we aim to generate candidates for chemical probes and publish them in open science format. (AU)

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Scientific publications (4)
(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)
AFONSO DE LIMA, CAROLINA; DE SOUZA BUENO, IAN LUCAS; NUNES SIQUEIRA VASCONCELOS, STANLEY; SCIANI, JULIANA MOZER; RUIZ, ANA LUCIA TASCA GOIS; FOGLIO, MARY ANN; DE CARVALHO, JOAO ERNESTO; BARBARINI LONGATO, GIOVANNA. Reversal of Ovarian Cancer Cell Lines Multidrug Resistance Phenotype by the Association of Apiole with Chemotherapies. PHARMACEUTICALS, v. 13, n. 10, . (18/09475-5, 16/06137-6)
FANTI, REBEKA C.; VASCONCELOS, STANLEY N. S.; CATTA-PRETA, CAROLINA M. C.; SULLIVAN, JARYD R. .; RIBOLDI, GUSTAVO P.; REIS, CAIO V. DOS; RAMOS, PRISCILA Z.; EDWARDS, ALED M.; BEHR, MARCEL A. .; COUNAGO, RAFAEL M.. A Target Engagement Assay to Assess Uptake, Potency, and Retention of Antibiotics in Living Bacteria. ACS INFECTIOUS DISEASES, v. 8, n. 8, p. 19-pg., . (13/50724-5, 14/50897-0, 18/09475-5)
SERAFIM, RICARDO A. M.; SORRELL, FIONA J.; BERGER, BENEDICT-TILMAN; COLLINS, ROSS J.; VASCONCELOS, STANLEY N. S.; MASSIRER, KATLIN B.; KNAPP, STEFAN; BENNETT, JAMES; FEDOROV, OLEG; PATEL, HITESH; et al. Discovery of a Potent Dual SLK/STK10 Inhibitor Based on a Maleimide Scaffold. Journal of Medicinal Chemistry, v. 64, n. 18, p. 13259-13278, . (18/09475-5, 16/25320-6)
SERAFIM, RICARDO A. M.; DE SOUZA GAMA, FERNANDO H.; DUTRA, LUIZ A.; DOS REIS, CAIO V.; VASCONCELOS, STANLEY N. S.; SANTIAGO, ANDRE DA SILVA; TAKARADA, JESSICA E.; DI PILLO, FULVIA; AZEVEDO, HATYLAS; MASCARELLO, ALESSANDRA; et al. Development of Pyridine-based Inhibitors for the Human Vaccinia-related Kinases 1 and 2. ACS Medicinal Chemistry Letters, v. 10, n. 9, p. 1266-1271, . (18/03359-3, 18/09475-5, 13/50724-5, 16/25320-6)

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