Exploring PI3K Pathway Inhibitors for Acute Myeloid Leukemia: A Drug-Repurposing Approach

Year 2023, , 205 - 212, 28.12.2023

Cansu Ergun , Buse Zeren Kiremitci , Gizem Arslantaş , Busenur Bozkurt , Gizem Ayna Duran , Yağmur Kiraz

https://doi.org/10.26650/experimed.1358971

Abstract

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.

Keywords

AML, repurposing, molecular docking, survival, PI3K pathway, VAV1

Ethical Statement

Here we declare that the manuscript including the original research ar4cle entitled Novel Drug Candidates Targeting PI3K Pathway in Acute Myeloid Leukemia Treatment does not require ethicscommitee approval.

Project Number

2209-A

Thanks

İzmir University of Economics

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