| Abstrakt: |
The FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) represents a distinct genetic mutation that characterizes acute myeloid leukaemia (AML). The breakpoint cluster region (BCR)-Abelson murine leukaemia (ABL) (BCR-ABL) is a key initiator of chronic myeloid leukaemia (CML) Hyperactivation of phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signalling is crucial in AML and CML pathogenesis. The recent development of tyrosine kinase inhibitors (TKIs) contributed to substantial improvements in leukaemia therapy. However, most leukaemia patients fail to completely recover and develop drug resistance after prolonged TKI therapy. Thymoquinone (TQ), a major ingredient of Nigella sativa seeds, has anti-tumour properties in a variety of cancers. However, the anti-leukemia effect of TQ was not extensively studied. Thus, the current research aims to identify TQ’s ability to bind on the active sites inFLT3-ITD, BCR-ABL, PI3K, Akt, and mTOR tyrosine kinases. The molecular docking of TQ toFLT3-ITD, BCR-ABL, PI3K, Akt, and mTOR was evaluated. Midostaurin; FLT3-ITD inhibitor, imatinib; BCR-ABL inhibitor, wortmannin; PI3K inhibitor, AZD5363; Akt inhibitor, and rapamycin; mTOR inhibitor were selected as positive controls. The findings revealed that TQ interacts with high affinities with the active site of PI3K(-7.02Kcal/mol), Akt(-6.4Kcal/mol), mTOR(-6.58Kcal/mol), FLT3- ITD(-6.35Kcal/mol), and BCR-ABL(-6.31Kcal/mol) and with low free binding energy to inhibit their enzymatic activities. In conclusion, TQ could potentially act as a TKI for FLT3- ITD, BCR-ABL, PI3K, Akt, and mTOR tyrosine kinases suggesting that TQ could act as a promising multi-targeted TKI for several tyrosine kinases for AML and CML treatment. [ABSTRACT FROM AUTHOR] |
