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Development of celular assays to measure and to discover the phenotypic consequences of chemical inhibition of Vaccinia-Related Kinase 1 (VRK1)

Grant number: 16/17469-0
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): November 01, 2016
Effective date (End): May 31, 2019
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Opher Gileadi
Grantee:Roberta Regina Ruela de Sousa
Host Institution: Centro de Biologia Molecular e Engenharia Genética (CBMEG). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil


One of the ways to get new medicines is to find the right targets, which are better predicted when the human biology is understood. To study human biology, tools such as genetic approaches and chemical inhibition are used to reveal the functions of a protein and together they can validate (or invalidate) a hypothetical therapeutic target. One of the protein classes that has been demonstrated to be good therapeutic target for many diseases is the protein kinase, firstly because protein kinases are involved in controlling many different cellular processes, including cell proliferation and apoptosis; secondly, kinases can be specifically targeted by small molecules, as evidenced by the increasing numbers kinases inhibitor approved by FDA, mostly in oncology; lastly, by the genetic link with human diseases by hundreds of human kinases from about 500 encoded by the genome. However, the kinases that have been studied are usually the same 50 from those studied 20 years ago. We might be missing a good target in those neglected protein kinases. To allow the scientific community to study the role of the less studied protein kinases and identify new therapeutic targets the SGC aims to develop chemical probes: potent, selective inhibitors of individual protein kinases, with well-defined activity in intact cells. In this project, I will develop and implement cell-based assays to show target engagements in cells, to measure the dose-response curves, and to probe the consequences of inhibition of the target kinase. This project will focus initially on VRK1, a serine-threonine kinase one of those less studied kinases. VRK1 is involved in cell cycle and DNA damage response and some studies suggest VRK1 as a target for cancer therapy. We will establish methods to validate chemical probes and to reveal the roles of VRK1 in cells. Later in the project, similar methods will be developed to systematically validate the cellular function of chemical probes targeting additional protein kinases. (AU)

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Scientific publications (5)
(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)
WELLS, CARROW; COUNAGO, RAFAEL M.; LIMAS, JUANITA C.; ALMEIDA, TUANNY L.; COOK, JEANETTE GOWEN; DREWRY, DAVID H.; ELKINS, JONATHAN M.; GILEADI, OPHER; KAPADIA, NIRAV R.; LORENTE-MACIAS, ALVARO; et al. SGC-AAK1-1: A Chemical Probe Targeting AAK1 and BMP2K. ACS Medicinal Chemistry Letters, v. 11, n. 3, p. 340-345, . (14/50897-0, 13/50724-5, 16/17469-0)
AGAJANIAN, MEGAN J.; WALKER, MATTHEW P.; AXTMAN, ALISON D.; RUELA-DE-SOUSA, ROBERTA R.; SERAFIN, D. STEPHEN; RABINOWITZ, ALEX D.; GRAHAM, DAVID M.; RYAN, MEAGAN B.; TAMIR, TIGIST; NAKAMICHI, YUKO; et al. WNT Activates the AAK1 Kinase to Promote Clathrin-Mediated Endocytosis of LRP6 and Establish a Negative Feedback Loop. CELL REPORTS, v. 26, n. 1, p. 79+, . (16/17469-0, 13/50724-5)
HENDERSON, SCOTT H.; SORRELL, FIONA; BENNETT, JAMES; FEDOROV, OLEG; HANLEY, MARCUS T.; GODOI, PAULO H.; DE SOUSA, ROBERTA RUELA; ROBINSON, SEAN; ASHALL-KELLY, ALEXANDER; NAVRATILOVA, IVA HOPKINS; et al. Discovery and Characterization of Selective and Ligand-Efficient DYRK Inhibitors. Journal of Medicinal Chemistry, v. 64, n. 15, p. 11709-11728, . (16/17469-0, 13/50724-5)
WELLS, CARROW I.; VASTA, JAMES D.; CORONA, CESEAR R.; WILKINSON, JENNIFER; ZIMPRICH, CHAD A.; INGOLD, MORGAN R.; PICKETT, JULIE E.; DREWRY, DAVID H.; PUGH, KATHRYN M.; SCHWINN, MARIE K.; et al. Quantifying CDK inhibitor selectivity in live cells. NATURE COMMUNICATIONS, v. 11, n. 1, . (14/50897-0, 13/50724-5, 16/17469-0)
HERNEISEN, ALICE L.; SIDIK, SAIMA M.; MARKUS, BENEDIKT M.; DREWRY, DAVID H.; ZUERCHER, WILLIAM J.; LOURIDO, SEBASTIAN. Identifying the Target of an Antiparasitic Compound in Toxoplasma Using Thermal Proteome Profiling. ACS Chemical Biology, v. 15, n. 7, p. 1801-1807, . (13/50724-5, 16/17469-0)

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