TY - JOUR T1 - Exploring PI3K Pathway Inhibitors for Acute Myeloid Leukemia: A Drug-Repurposing Approach AU - Kiraz, Yağmur AU - Ergun, Cansu AU - Kiremitci, Buse Zeren AU - Arslantaş, Gizem AU - Bozkurt, Busenur AU - Ayna Duran, Gizem PY - 2023 DA - December DO - 10.26650/experimed.1358971 JF - Experimed PB - Istanbul University WT - DergiPark SN - 2667-5846 SP - 205 EP - 212 VL - 13 IS - 3 LA - en AB - Objective: Acute myeloid leukemia (AML) is a malignant disease characterized by the uncontrolled growth, differentiation, and proliferation of immature hematopoietic cells. Patients with AML often have poor survival rates, which are associated with specific gene mutations in FLT3, CEBPA, and NPM1. The phosphatidylinositol 3-kinase (PI3K) pathway, a lipase pathway, is activated in many malignancies, including AML. Given the low survival rates in AML, this study identified candidate drugs that could inhibit the PI3K pathway, thereby offering a potential treatment for AML, by using a drug-repurposing approach.Materials and Methods: Online bioinformatics tools were utilized to identify pathway-related genes and FDA-approved drugs. Subsequently, molecular docking was performed to determine the binding affinity values. Important genes were identified by evaluating their impact on survival and their aberrant expression in the tumor. In this study, genes such as VAV1, GSK3B, MTOR, PDPK1, PRR5, TSC2, AKT3, and CREB1 were determined and docked with their potential inhibitors. Particular attention was paid to VAV1 because there were no known potential VAV1 inhibitors used in AML.Results: The docking results were ranked, and the proposed gene–drug pairs were identified as tideglusib and fostamatinib for the inhibition of GSK3B, pimecrolimus and fostamatinib for the inhibition of MTOR, and fostamatinib for the inhibition of PDPK1. Furthermore, nebivolol, darifenacin, dihydroergotamine, libanserin and entereg were identified as potential inhibitors of VAV1 in AML.Conclusion: To sum up, most effective gene–drug pairs according to binding affinities were proposed as candidate inhibitor drugs for AML. KW - AML KW - repurposing KW - molecular docking KW - survival KW - PI3K pathway KW - VAV1 CR - 1. Short NJ, Rytting ME, Cortes JE. Acute myeloid leukaemia. Lancet 2018; 392(10147): 593-606. google scholar CR - 2. Hasserjian RP. Acute myeloid leukemia: advances in diagnosis and classification. Int J Lab Hematol 2013; 35(3): 358-66. google scholar CR - 3. 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