Aurora Kinase A Inhibitors Reverse Rare Form of Leukemia in Mouse Model

The disease is characterized by an overload of immature white blood cells that – due to overexpression of Aurora A kinase - cannot mature into specialized cells.

Aurora A kinase (serine/threonine-protein kinase 6) is an enzyme that in humans is encoded by the AURKA gene. It is a member of a family of mitotic serine/threonine kinases and has been linked to important processes during mitosis and meiosis whose proper function is integral for healthy cell proliferation. Aurora A is activated by one or more phosphorylations and its activity peaks during the G2 phase to M phase transition in the cell cycle. It is associated with centrosome maturation and separation and thereby regulates spindle assembly and stability. Aurora A kinase dysregulation has been associated with high occurrence of cancer. For example, one study showed over-expression of Aurora A kinase in 94% of the invasive tissue growth in breast cancer, while surrounding, healthy tissues had normal levels of Aurora A kinase expression.

In the first stage of a study that was published in the August 3, 2012, issue of the journal Cell investigators at Northwestern University (Chicago, IL, USA) used a high-content image-based screen to identify small-molecule probes that could induce the formation of megakaryocytic leukemia cells.

They identified five networks of kinases that regulated the switch to polyploidy and uncontrolled replication. Moreover, a screen of over 9,000 compounds showed that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. An integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF was Aurora kinase A.

The known Aurora kinsase A inhibitor MLN8237 (Alisertib), was tested in a mouse AMKL model. The drug induced polyploidization and expression of mature megakaryocyte markers in acute megakaryocytic leukemia (AMKL) blasts and displayed potent anti-AMKL activity in vivo.

"Alisertib was really potent against the proliferation of cancer cells," said senior author Dr. John Crispino, professor of hematology and oncology at Northwestern University. "We were incredibly excited when we found that the drug we predict will reverse AMKL is already far along in clinical development. The fact that we do not have to start from scratch means we could be years closer to finding an effective therapy."

"Dimethylfasudil could be useful against AMKL and tolerated better by patients," said Dr. Crispino. "However, alisertib is moving forward now because there is urgent need and the drug is available. Meanwhile, work is continuing to develop dimethylfasudil into an acceptable anticancer drug for clinical trials, which may take two to three years."

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