Akut miyeloid lösemiyi hedeflemek için in silico ve in vitro çalışmalar kullanılarak Dalak Tirozin Kinaz enziminin SH2 alanının araştırılması

Acute Myeloid Leukemia (AML) is a clonal malignancy characterized by genetic and epigenetic abnormalities and one molecule that has emerged as a potential therapeutic target in this complex disease is Spleen Tyrosine Kinase (Syk) which consists of two SH2 domains at its amino terminus followed by a catalytically active kinase domain. Recent studies in cancer treatment methods to prevent the activation of abnormal proteins that lead to cancer have revealed that SH2 domains are also important targets in addition to active kinase domains. In this study, candidate inhibitors were identified through in silico studies by screening two libraries, COCONUT and ENAMINE. In vitro binding tests were then conducted for two candidate inhibitors selected from the ENAMINE library (Z260816155 and z2155444005), and binding was confirmed in vitro in HEK293 cells using FRET technology and Differential Scanning Fluorimetry Assay (DSF). Finally, the aim was to investigate the biological activities of inhibiting protein-protein interactions by targeting the SH2 domains of Syk on AML cells. The candidate inhibitors used decreased cell viability at low micromolar concentrations (1-25 µM) in THP-1 and HL-60 cells and, in a correlated manner, induced apoptosis and caused cell cycle arrest cells compared to control cells. Furthermore, they modulated the gene expression of TNF-α and IL-1β and effectively suppressed the anti-apoptotic proteins Bcl-2 and Bcl-xL.