An ATP analog DIMA elicits a synthetic lethal effect in cells overexpressing the MYC oncoprotein by acting as a dual inhibitor of MKLP2 and Aurora-Bkinase

Overview

J. Michael Bishop Institute of Cancer Research (MBICR) Synthetic lethal therapies represent an emerging direction of anticancer drug development. We have recently identified a mitotic regulator, the motor kinesin-like protein MKLP2, as a synthetic lethal target in cells overexpressing the Myc oncoprotein. Currently, the Myc oncoprotein lacks effective pharmacological inhibitors. Based on the structure of MKLP2, we used a computationbased approach to design an ATP analog that elicits the dual inhibition of MKLP2 and Aurora Kinase B, named DIMA, as a potential inhibitor of the mitotic regulator. Upon exposure to the chemically synthesized DIMA, cells were initially arrested in early mitosis and then developed polyploidy or underwent apoptosis. Immunofluorescence staining of drug-treated cells revealed that DIMA efficiently inhibited both MKLP2 and Aurora-Bkinase without much discrimination. This inhibition apparently led to a failure of cytokinesis because both MKLP2 and aurora-Bare pivotal regulators of cytokinesis. Cells suffering cytokinetic failure underwent repeated runs of DNA synthesis in the absence of cytokinesis, resulting in polyploidy. In contrast, Aurora-A was not inhibited. Collectively, these data indicate that DIMA is a novel dual inhibitor of MKLP2 and Aurora-B. This compound has great potential in furthering the field of anti-cancer drug development as a synthetic lethal therapeutic that kills cells overexpressing MYC. Reducing the Impact of Dust Accumulation on Photovoltaic (PV) Solar Panels by providing Vibration and Airflow Zehao(Tony) Yan g The Walker School Atlanta, Georgia

Competition history

• JSHS 2020 Category not listed

Resources

• National JSHS abstract book ↗

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