Identifikacija malih molekula s inhibirajućim djelovanjem na onkogeni mutant tirozinsko kinaznog receptora FGFR4 metodom MaMTH-DS

master's thesis

• Title (english): Identification of small molecule inhibitors of oncogenic FGFR4 receptor tyrosine kinase mutant using MaMTH-DS method
• Author: Nika Vučković
• Mentor: Igor Štagljar https://orcid.org/0000-0002-5260-3327 (mentor)
• Mentor: Petra Korać (mentor)
• Committee member: Petra Korać (predsjednik povjerenstva)
• Committee member: Sofia Ana Blažević (član povjerenstva)
• Committee member: Tomislav Ivanković (član povjerenstva)
• Committee member: Duje Lisičić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2019-04-17, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology

Abstract

Stanice primaju signale iz (mikro)okoliša putem stanične membrane. Te signale prepoznaju specifični receptori što se prevodi u stanični odgovor. Jedan od sustava koji omogućava takvu signalizaciju jest putem tirozinskih kinaznih receptora (RTK). RTK su membranski proteini koji su regulatori središnjih staničnih procesa uključujući proliferaciju, diferencijaciju, stanično preživljenje, kontrolu staničnog ciklusa i metabolizam. Posljedično, za konstitutivna i aberantna aktivacija RTK-a i nizvodnih signalnih putova sudjeluju u tumorigenezi zbog remećenjea navedenih procesa. Receptor fibroblastnog faktora rasta 4 (FGFR4) je RTK, čija je aberantna regulacija povezana s raznim karcinomima i sposobnošću metastaziranja. Njegova mutacija V550E se smatra aktivirajućom kod rabdomiosarkoma, tumora dječje dobi s neodgovarajućom terapijom u kasnijim stadijima. Kako znanje o molekularnoj osnovi karcinoma raste, omogućava razvoj novih, ciljanih terapija. Probir visoke protočnosti pristup je otkrivanju lijekova koji uključuje biokemijske testove i testove koji se temelje na korištenju stanica za probir zbirki spojeva u svrhu nalaženja specifičnih ciljanih pogodaka. Cilj ovog istraživanja bio je identificirati male molekule s inhibirajućim djelovanjem specifičnim za FGFR4 V550E korištenjem testa MaMTH, nedavno razvijene tehnologije za istraživanje interakcija membranskih proteina, modificirane u visokoprotočnu varijantu, MaMTH-DS. Testirana je zbirka od 5570 spojeva te je za pet malih molekula identificirano inhibirajuće djelovanje specifično za mutirani receptor FGFR4.

Abstract (english)

Cells receive signals from beyond the cell membrane which are detected by specific receptors and that renders a cellular response. One of the systems that enable such signalling is through receptor tyrosine kinases (RTKs). RTKs are membrane proteins which have been proven as crucial regulators of pivotal cellular processes including proliferation, differentiation, cell survival, cell cycle control and metabolism. Consequently, constitutive and aberrant activation of RTKs and downstream pathways is shown to lead to tumorigenesis through disruption of these processes. Fibroblast growth factor receptor 4 (FGFR4) is an RTK whose aberrant regulation is associated with various cancers and the ability to metastasize. Its mutation V550E is considered activating in rhabdomyosarcoma, a childhood tumor with inadequate therapy for later stages. As knowledge of molecular basis of cancer expands it enables development of novel, targeted therapies. High-throughput screening approach to drug discovery involves biochemical and cell-based assays to screen collections of compounds in order to find specific hits on a target. Aim of this study was to identify small molecule inhibitors specific to the FGFR4 V550E using MaMTH assay, a recently developed technology for mapping interactions of membrane proteins, modified into a high-throughput drug screening method, MaMTH-DS. Collection of 5570 compounds was tested and five were identified as mutant specific inhibitory hits.

• Keywords: FGFR4 V550E; MaMTH; mutant specific hits; inhibitory hits
• Keywords (english): FGFR4 V550E; MaMTH; mutant specific hits; inhibitory hits
• Language: croatian
• URN:NBN: urn:nbn:hr:217:095386
• Study programme: Title: Molecular Biology; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra molekularne biologije (magistar/magistra molekularne biologije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access; Embargo expiration date: 2021-04-17
• Created on: 2019-12-04 14:20:25