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Načrtovanje selektivnih zaviralcev Hsp90β s pirolamidnim skeletom
ID Povše, Tjaša (Author), ID Tomašič, Tihomir (Mentor) More about this mentor... This link opens in a new window

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Abstract
Protein toplotnega šoka Hsp90 je 90 kDa velik molekulski šaperon, odgovoren za številne normalne in patogene procese v celici. Njegovo izražanje se poveča, če je celica izpostavljena stresnim pogojem. V celici se nahaja v štirih izoformnih oblikah: v citoplazmi v obliki Hsp90α in Hsp90β, v endoplazemskem retikulumu v obliki Grp94 in v mitohondriju v obliki Trap1. Hsp90 predstavlja zanimivo terapevtsko tarčo, saj ima bistveno vlogo pri maligni transformaciji celic, pri razvoju nevrodegenerativnih boleznih, virusnih in glivičnih infekcijah. Rak je kompleksna družina različnih bolezni, povezanih z nenormalno rastjo in delitvijo celic. Kljub velikim napredkom pri zdravljenju predstavljajo rakava obolenja še vedno enega od glavnih vzrokov smrti v razvitem svetu. Zato je odkrivanje novih protitumornih učinkovin izjemnega pomena za zagotavljanje uspešnega zdravljenja rakavih obolenj v prihodnosti. Hsp90 predstavlja zanimivo tarčo v terapiji raka, saj je njegova ekspresija v rakavih celicah tudi do 10-krat višja kot v normalnih celicah. V zadnjih letih so odkrili mnoge zaviralce Hsp90, kljub temu pa do danes še noben ni bil odobren za uporabo v terapiji. V okviru magistrske naloge smo načrtovali nove selektivne zaviralce Hsp90β na osnovi znanega zaviralca IZS274 s pirolamidnim skeletom, pri katerem smo spreminjali karboksamidni in piperidin-4-olni fragment spojine. Načrtovanje analogov smo izvedli tako, da smo najprej poravnali vse kristalne strukture kompleksov med Hsp90 in zaviralci, nato pa na osnovi prekrivanja zaviralcev z vezavno konformacijo IZS274 v aktivnem mestu zamenjali karboksamidni ali piperidin-4-olni del s fragmenti iz kristalnih struktur. Z vpeljavo novih fragmentov smo želeli preveriti, kako vpliva vpeljava aromatskih substituentov, lipofilnih substituentov in dodatnih bazičnih centrov na afiniteto in selektivnost vezave na Hsp90β. Z načrtovanimi spojinami smo izvedli molekulsko sidranje v vezavno mesto Hsp90β. Izbrane spojine z visoko vrednostjo cenilne funkcije so sintetizirali raziskovalci na Fakulteti za farmacijo. Na osnovi eksperimentalnih vrednosti Kd smo ugotovili, da spojine z aromatskimi substituenti kljub visoki oceni cenilne funkcije ne izkazujejo afinitete do Hsp90β, lipofilni substituenti pa povečajo selektivnost napram Hsp90β v primerjavi z Hsp90α, kar so pomembni izsledki za nadaljnje načrtovanje in razvoj selektivnih zaviralcev Hsp90β kot potencialnih protirakavih učinkovin.

Language:Slovenian
Keywords:Hsp90, odziv toplotnega šoka, rak, selektivnost, zaviralec
Work type:Master's thesis/paper
Organization:FFA - Faculty of Pharmacy
Year:2022
PID:20.500.12556/RUL-141027 This link opens in a new window
Publication date in RUL:22.09.2022
Views:226
Downloads:28
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Secondary language

Language:English
Title:Design of selective Hsp90β inhibitors with pyrrolamide scaffold
Abstract:
The Hsp90 heat shock protein is a 90 kDa molecular chaperone responsible for normal functions and pathogenic processes in cells. Its expression increases when the cell is exposed to stress conditions. It occurs in cells in four isoforms: in the cytoplasm as Hsp90α and Hsp90β, in the endoplasmic reticulum as Grp94, and in mitochondria as Trap1. Hsp90 represents an interesting target because of its important role in malignant cell transformation, development of neurogenerative diseases, viral and fungal infections. Cancer is a complex family of diverse diseases associated with abnormal growth and cell division, leading to loss of control over growth, cell division, and death. Despite major advances in healthcare, cancer is still one of the leading causes of death in developed countries. Therefore, research into new anti-cancer drugs is of paramount importance to ensure successful treatment in the future. Hsp90 represents an interesting target for cancer therapy because it is ten times more abundant in cancer cells than in normal cells. Many Hsp90 inhibitors have been discovered in recent years, but none has yet come to market. In this Master's thesis, we designed new selective Hsp90β inhibitors based on the known inhibitor IZS274 with the pyrrolamide scaffold, in which the carboxamide and piperidin-4-ol fragments were modified. We designed the analogs by first aligning all the crystal structures of the complexes between Hsp90 and the inhibitors and then, based on the overlap of the inhibitors with the binding conformation of IZS274 in the active site, replacing the carboxamide or piperidin-4-ol moiety with fragments from the crystal structures. By introducing new fragments, we aimed to investigate how the introduction of aromatic substituents, lipophilic substituents, and additional basic centers affects the affinity and selectivity of binding to Hsp90β. Molecular docking of the designed compounds in the binding site of Hsp90β was performed. Selected compounds with high value of scoring function were synthesized by researchers from the Faculty of Pharmacy. On the basis of the experimental Kd values, we found that compounds with aromatic substituents, despite the high assessment function, do not show affinity for Hsp90β, lipophilic substituents increased selectivity toward Hsp90β compared with Hsp90α, which are important findings for further design and development of selective Hsp90β inhibitors as potential anticancer agents.

Keywords:Hsp90, heat shock response, cancer, selectivity, inhibitor

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