Discovery of novel AQP3-inhibitors
(2025) KASM05 20251Centre for Analysis and Synthesis
- Abstract
- Aquaporins (AQPs) are a family of transmembrane proteins, mainly mediating water transport over the cell membrane in various parts of the body. The aquaporins AQP3 and AQP7 are both part of the subfamily aquaglyceroporins, which apart from water conduct small non-polar solutes such as glycerol. AQP3 overexpression or malfunction has been connected to skin and lung cancer and potential AQP3 inhibitors have also been in discussion for nephrological applications. Meanwhile, AQP7 inhibitors are holding promise as potential treatments against breast cancer, atopic dermatitis and oedema.
Starting from Z433927330, a known inhibitor against AQP3 and AQP7, the aim of this master thesis was to synthesise analogues with improved inhibitory... (More) - Aquaporins (AQPs) are a family of transmembrane proteins, mainly mediating water transport over the cell membrane in various parts of the body. The aquaporins AQP3 and AQP7 are both part of the subfamily aquaglyceroporins, which apart from water conduct small non-polar solutes such as glycerol. AQP3 overexpression or malfunction has been connected to skin and lung cancer and potential AQP3 inhibitors have also been in discussion for nephrological applications. Meanwhile, AQP7 inhibitors are holding promise as potential treatments against breast cancer, atopic dermatitis and oedema.
Starting from Z433927330, a known inhibitor against AQP3 and AQP7, the aim of this master thesis was to synthesise analogues with improved inhibitory properties and develop the SAR of AQP3 and AQP7. Firstly, molecular dynamics simulations were conducted to determine possible binding interactions between analogues and AQP3. From these results promising potential inhibitors were identified and synthetic schemes were laid out. The desired compounds were then synthesised and tested for their inhibitory properties on AQP3-mediated cellular water permeability in a cellular assay with Chinese Hamster Ovary (CHO) cells with overexpressed AQP3. Based on the results from the inhibition assay, new synthetic targets were identified and then synthesised in an iterative process, which was repeated twice.
In total, Z433927330 and 14 analogues were successfully synthesised and tested for AQP3 inhibition. Of these analogues, six were inhibitors of AQP3, all with a higher IC50 value than the literature value of Z433927330. However, five of them showed a significantly higher efficacy. These results gave interesting insights with respect to the inhibitory interactions of Z433927330 with AQP3.
These insights can be used to further develop even more potent AQP3 inhibitors, paving the way for a future clinical application. (Less) - Popular Abstract (Swedish)
- Vatten är nödvändigt för att den mänskliga kroppen ska fungera. För att vattnet ska kunna transporteras in och ut ur cellerna behöver det komma igenom cellmembranet, vilket det bland annat gör via en särskild klass av proteiner som fungerar som vattenkanaler – akvaporinerna.
Akvaporiner finns överallt i vår kropp och är viktiga för många biologiska funktioner såsom metabolism och återfuktning av huden. Sedan deras upptäckt 1993 har 13 olika typer av akvaporiner med olika funktioner identifierats, i det här arbetet ligger fokus på akvaporin-3 (AQP3) och akvaporin-7 (AQP7).
AQP3 har kopplats till flera cancerformer, framförallt lung- och hudcancer, där en inhibitor till AQP3 tros ha potential att utvecklas till ett nytt cancerläkemedel.... (More) - Vatten är nödvändigt för att den mänskliga kroppen ska fungera. För att vattnet ska kunna transporteras in och ut ur cellerna behöver det komma igenom cellmembranet, vilket det bland annat gör via en särskild klass av proteiner som fungerar som vattenkanaler – akvaporinerna.
Akvaporiner finns överallt i vår kropp och är viktiga för många biologiska funktioner såsom metabolism och återfuktning av huden. Sedan deras upptäckt 1993 har 13 olika typer av akvaporiner med olika funktioner identifierats, i det här arbetet ligger fokus på akvaporin-3 (AQP3) och akvaporin-7 (AQP7).
AQP3 har kopplats till flera cancerformer, framförallt lung- och hudcancer, där en inhibitor till AQP3 tros ha potential att utvecklas till ett nytt cancerläkemedel. Det är dessutom möjligt att en AQP3-inhibitor kan utvecklas till njurläkemedel. AQP7 har visats vara en viktig faktor vid bröstcancer och har även kopplats till olika hudsjukdomar.
Detta projekt har fokuserat på att syntetisera så kallade analoger till en känd kemisk förening, Z433927330, som visats binda till och inhibera AQP3 och AQP7. Målet med detta arbete har varit att hitta substanser som kan användas i framtida läkemedel samt förstå bindningsinteraktioner till akvaporiner.
Först simulerades bindningen mellan olika analoger och AQP3 på datorn, för att få en uppfattning om hur olika delar av molekylen kan interagera med akvaporinen. Sedan bestämdes ett antal målföreningar som syntetiserades i labbet och testades med avseende på bindning till AQP3. Testerna genomfördes i celler från kinesiska dvärghamstrar, där vattentransporten över membranet kvantifierades via ljusutsändning. Baserat på resultaten från testen bestämdes nya målföreningar och processen började om från början.
Totalt syntetiserades och testades 14 analoger av Z433927330 för AQP3-inhibering. Av dessa visade 6 analoger på inhibering, ingen vid en lika låg koncentration som Z433927330, men 5 av 6 kunde inhibera akvaporinen betydligt effektivare, vilket innebär att proteinet släpper igenom mindre vatten. Från dessa resultat kan man dra intressanta slutsatser gällande bindning till AQP3, som kan underlätta utvecklandet av mer potenta inhibitorer som slut kan leda till en klinisk applikation. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9206748
- author
- Brakebusch, Nils LU
- supervisor
-
- Ulf Nilsson LU
- Karin Lindkvist LU
- organization
- course
- KASM05 20251
- year
- 2025
- type
- H2 - Master's Degree (Two Years)
- subject
- keywords
- Medicinal Chemistry, Organic Chemistry, Drug Design, Drug Development, Aquaporin Inhibitors
- language
- English
- id
- 9206748
- date added to LUP
- 2025-06-30 11:16:41
- date last changed
- 2025-06-30 11:16:41
@misc{9206748,
abstract = {{Aquaporins (AQPs) are a family of transmembrane proteins, mainly mediating water transport over the cell membrane in various parts of the body. The aquaporins AQP3 and AQP7 are both part of the subfamily aquaglyceroporins, which apart from water conduct small non-polar solutes such as glycerol. AQP3 overexpression or malfunction has been connected to skin and lung cancer and potential AQP3 inhibitors have also been in discussion for nephrological applications. Meanwhile, AQP7 inhibitors are holding promise as potential treatments against breast cancer, atopic dermatitis and oedema.
Starting from Z433927330, a known inhibitor against AQP3 and AQP7, the aim of this master thesis was to synthesise analogues with improved inhibitory properties and develop the SAR of AQP3 and AQP7. Firstly, molecular dynamics simulations were conducted to determine possible binding interactions between analogues and AQP3. From these results promising potential inhibitors were identified and synthetic schemes were laid out. The desired compounds were then synthesised and tested for their inhibitory properties on AQP3-mediated cellular water permeability in a cellular assay with Chinese Hamster Ovary (CHO) cells with overexpressed AQP3. Based on the results from the inhibition assay, new synthetic targets were identified and then synthesised in an iterative process, which was repeated twice.
In total, Z433927330 and 14 analogues were successfully synthesised and tested for AQP3 inhibition. Of these analogues, six were inhibitors of AQP3, all with a higher IC50 value than the literature value of Z433927330. However, five of them showed a significantly higher efficacy. These results gave interesting insights with respect to the inhibitory interactions of Z433927330 with AQP3.
These insights can be used to further develop even more potent AQP3 inhibitors, paving the way for a future clinical application.}},
author = {{Brakebusch, Nils}},
language = {{eng}},
note = {{Student Paper}},
title = {{Discovery of novel AQP3-inhibitors}},
year = {{2025}},
}