3:11 PM
Mar 07, 2018
 |  BC Extra  |  Preclinical News

Selectively inhibiting GSK3's double genes for AML

Researchers at the Broad Institute of MIT and Harvard and colleagues found a way to design highly selective glycogen synthase kinase 3 inhibitors that target one of two forms of the gene. The approach could help treat acute myelogenous leukemia while circumventing toxicities associated with dual inhibition of GSK3 paralogs.

GSK3 is encoded across GSK3 alpha (GSK3A) located on chromosome 19 and GSK3 beta (GSK3B) located on chromosome 3. Previous research suggests both contribute to the development of several diseases, including AML, but little is known about the role of each paralog in disease. Since the genes' amino acid sequences are so similar, targeting just one of them has proven a challenge.

Additionally, dually inhibiting GSK3A and GSK3B boosts expression of beta-catenin (CTNNB1), a notoriously undruggable protein that is highly expressed in several tumors, including metastatic colorectal cancer (mCRC) (see BioCentury Innovations, May 31, 2017).

The team previously showed that genetic suppression of GSK3A decreased tumor progression without increasing CTNNB1 levels in mouse models of AML.

In this study published in Science Translational Medicine, the researchers discovered a single -- but key -- difference in the adenosine triphosphate (ATP)-binding domain's amino acid sequence of the two paralogs that allowed them to model and synthesize GSK3 inhibitors with binding preference for either GSK3A or GSK3B.

In human AML cell lines and five primary AML patient samples, the tool compound GSK3A inhibitor decreased cancer colonies compared with vehicle, without affecting normal hematopoietic cell growth.

In the cell lines, the GSK3A inhibitor did not increase CTNNB1 levels, whereas a tool compound GSK3B inhibitor increased CTNNB1 levels in two of the cell lines.

In three mouse models of AML, the GSK3A inhibitor increased survival and decreased disease progression compared with vehicle. The GSK3A inhibitor also increased survival and decreased leukemia progression when compared with the GSK3B inhibitor or a dual GSK3 inhibitor in two of the models.

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