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Design and synthesis of STK10 and VRK2 kinase inhibitors

Grant number: 19/25008-0
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): March 01, 2020
Effective date (End): October 31, 2023
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Organic Chemistry
Principal Investigator:Ronaldo Aloise Pilli
Grantee:Ian de Toledo
Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated scholarship(s):22/00759-6 - Design and synthesis of small molecules targeting transcription factors NPAS1 and NPAS3, BE.EP.DR


Chemical probes are important tools for functional study of biomacromolecules. In the context of the development of new drugs, these tools are used in the validation or invalidation of essential therapeutic targets for the progression of diseases. The development of a chemical probe involves structural optimization by Medicinal Chemistry focusing on potency and selectivity optimization, and Chemical Biology for the compound profile characterization and biomacromolecule functional studies. Currently, there is an increasing interest in the development of high quality chemical probes for kinases since from more than 500 known kinases, only around 40 have been well characterized regarding its function. The kinase protein family has great therapeutic potential and today there are 39 approved inhibitors being used in clinic for the treatment of a range of diseases. In this project we plan to develop potent and selective inhibitors, aiming to achieve the chemical probe criteria, for two understudied kinases: the STK10 and the VRK2 kinases. Regarding the STK10 kinase, we will explore the naphthalene and the piperidine moieties of the 2,4,5-trisubstituted imidazole inhibitors for potency optimization. Consedering the VRK2 kinase, we hope to validate the chemical scaffold 1,3,6-trisubstituted pyrazole[3,4-d]pyridmidines as potential inhibitors and then develop potent and selective inhibitors. This project will be developed in collaboration with the Structural Genomics Consortium (SGC) hubs at UNICAMP and at the University of Oxford where enzymatic and biophysical assays will be performed as well as the cellular assays and co-crystallization experiments. (AU)

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Scientific publications
(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)
MEIRELLES, MATHEUS A.; DE TOLEDO, IAN; THUROW, SAMUEL; BARREIRO, GABRIELA; COUNAGO, RAFAEL M.; PILLI, RONALDO A.. Functionalization of 2,4-Dichloropyrimidines by 2,2,6,6-Tetramethylpiperidyl Zinc Base Enables Modular Synthesis of Antimalarial Diaminopyrimidine P218 and Analogues. Journal of Organic Chemistry, v. 88, n. 13, p. 13-pg., . (14/50897-0, 19/25008-0, 19/20735-1, 19/13104-5, 13/50724-5)

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