A POTENTIAL TARGET FOR DEVOLOPING BROAD SPECTRUM ANTICANCERS: HEXOKINASE-II

Year 2022, Volume: 46 Issue: 1, 182 - 192, 29.01.2022

Mevlüt Akdağ Azime Berna Özçelik

https://doi.org/10.33483/jfpau.978805

Abstract

Objective: As a result of increased need of glucose, reprogramming the metabolic pathways related to respiration is a significant change in cancer cells which differs them from normal cells and this change is known as “Warburg Phenomenon” because firstly reported by Otto Warburg in 1920s. Increased glycolysis in cancer cells makes glycolysis pathway an important target for cancer tratment. Hexokinase (HK), first and one of the rate limiting steps of glycolitic pathway, is an important target through this perspective since the prominent phenotype in cancer cells is HK-II, this makes the development of new therapies against this isozyme possible. Using medicinal chemistry approaches new inhibitors can be designed by determining the heterocycles and functional groups providing selectivity against this isozyme.

Result and Discussion: Selective therapies against HK-II are based on inhibition, regulation, and expression of this enzyme. Small molecules targeting HK-II provide a basis for developing novel molecules. The discovery of selective inhibitors of HK-II is a promising progress for using selective and wide spectrum agents against cancer in the future cancer therapy.

Keywords

Cancer, chemotherapy, glycolysis, hexokinase, Warburg Effect

GENİŞ SPEKTRUMLU ANTİKANSER BİLEŞİKLER GELİŞTİRMEYE YÖNELİK POTANSİYEL BİR HEDEF: HEKSOKİNAZ-II

Abstract

Amaç: Kanser hücrelerinin glikoza duydukları ihtiyaç sonucu solunumla ilgili metabolik yolaklarını yeniden düzenlemesi, kanser hücrelerini normal hücrelerden ayıran önemli değişimlerden biridir ve bu değişim ilk olarak 1920’li yıllarda Otto Warburg tarafından rapor edildiği için “Warburg Fenomeni” olarak bilinir. Kanser hücrelerindeki artmış glikoliz, bu yolağı önemli bir kanser hedefi haline getirir. Glikolizin ilk ve hız kısıtlayıcı basamaklarından biri olan Heksokinaz (HK) enzimi bu açıdan önemli bir hedeftir ve kanser hücrelerinde karşımıza çıkan HK-II’nin baskın olduğu fenotip bu izozime yönelik tedavilerin geliştirilmesini mümkün kılar. Medisinal kimya yaklaşımları kullanılarak bu izozime karşı selektivite sağlayan heterosiklik yapılar ve fonksiyonel gruplar belirlenerek yeni inhibitörler dizayn edilebilir.

Sonuç ve Tartışma: HK-II’ye yönelik selektif tedaviler enzimin inhibisyonunu, regülasyonunu ve ekspresyonunu temel alır. HK-II’yi hedef alan küçük moleküller yeni moleküllerin keşfi için bir temel oluşturmaktadır. HK-II’ye selektif inhibitörlerin keşfi, kansere yönelik spesifik ve geniş spektrumlu ajanların gelecekte tedavide yer alabilmesi bakımından umut verici bir gelişmedir.

Keywords

Glikoliz, heksokinaz, kanser, kemoterapi, Warburg Etkisi

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