Establishing the Role of Thymoquinone as Potential Inhibitor of Mutant Oncoproteins in FLT۳/RAS/RAF/MEK/ERK Pathway against Acute Myeloid Leukemia

Mutations in FLT۳ prompt hyperactivation of RAS/RAF/MEK/ERK growth signalling. The FLT۳-D۸۳۵Y mutation confers resistance to FLT۳ inhibitors for acute myeloid leukemia (AML) therapy. The KRAS-G۱۲C and BRAF-V۶۰۰E are frequent mutations in several cancers. While inhibitors against RAS, RAF, MEK, and ERK are available, they are often unsuccessful against BRAF or KRAS mutations with reported toxicity rates. This study evaluates the potential of thymoquinone (TQ), a phytochemical obtained from Nigella sativa seed, to function as an inhibitor of FLT۳-D۸۳۵Y, KRAS-G۱۲C, BRAF-V۶۰۰E, MEK, and ERK and to modify the expressions of genes related to RAS/RAF/MEK/ERK signaling in MV۴-۱۱ AML cells. The cells were incubated with TQ and we utilized RT-qPCR to measure the target genes’ mRNA levels. Molecular docking of TQ and reference inhibitors to FLT۳-D۸۳۵Y, KRAS-G۱۲C, BRAF-V۶۰۰E, MEK, and ERK proteins was examined with calculations of binding energies. TQ produced significantly downregulated K-RAS, B-RAF, MEK۱, and ERK۲ expressions. TQ also docked to FLT۳-D۸۳۵Y, KRAS-G۱۲C, BRAF-V۶۰۰E, MEK۱, and ERK۲ with high binding affinities and low docking scores. The study identifies TQ as an inhibitor of multiple target mutations that could combat resistance to FLT۳-D۸۳۵Y, KRAS-G۱۲C, and BRAF-V۶۰۰E inhibitors, aiding in the improvement of AML therapy.

کلیدواژه ها:

FLT۳-D۸۳۵Y ، KRAS-G۱۲C ، BRAF-V۶۰۰E ، MEK۱ ، ERK۲ ، phytochemicals ، Docking