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Design and synthesis of covalent inhibitors for the protein kinase TTK

Grant number: 18/23322-7
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): March 01, 2019
Effective date (End): February 29, 2020
Field of knowledge:Physical Sciences and Mathematics - Chemistry
Principal Investigator:Katlin Brauer Massirer
Grantee:Ricardo Augusto Massarico Serafim
Supervisor abroad: Stefan Laufer
Home Institution: Centro de Biologia Molecular e Engenharia Genética (CBMEG). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Local de pesquisa : Eberhard Karls Universität Tübingen, Germany  
Associated to the scholarship:16/25320-6 - Design and synthesis of inhibitors for understudied protein kinases related to RNA and epigenetics, BP.PD

Abstract

Protein kinases comprise a large family of proteins responsible for ATP-dependent phosphorylation. This event represents the main post-translation signaling mechanism, controlling most of the human cellular processes. The human genome has approximately 550 kinase proteins (kinome), but only about 15% have been extensively studied, showing the need to expand development of kinase inhibitors in the pharmaceutical industry and academia. Considering the importance of the protein kinase TTK for many kinds of cancers and that TTK is an attractive target for development of covalent inhibitors, the aim of this project is to design and synthetize the first covalent inhibitors for the protein kinase TTK using a structure-based approach. The initial template scaffolds were chosen based on previous computational analyses using all the TTK co-crystal structures available in Protein Data Bank (PDB), the structure of the covalent inhibitor BLU9931 in complex with the similar protein kinase FGFR4, and the geometry of the ortho-position substituted group toward the nucleophilic site (Cys604). The acrylamide will be the warhead to be used initially, which can be replaced if the evaluation of other electrophilic functional groups is necessary. The determination of the covalent inhibition as well as the crystallography of the ligand-target complexes and biological/cell assays will be performed at Structural Genomics Consortium at UNICAMP - SGC/UNICAMP. We expect to generate highly potent and selective inhibitors and to publish them in the open science context of the SGC (PITE FAPESP 2013/50724-5).