Evaluation of Improved Glycogen Synthase Kinase-3α Inhibitors in Models of Acute Myeloid Leukemia

The challenge for glycogen synthase
kinase-3 (GSK-3) inhibitor
design lies in achieving high selectivity for one isoform over the
other. The therapy of certain diseases, such as acute myeloid leukemia
(AML), may require α-isoform specific targeting. The scorpion
shaped GSK-3 inhibitors developed by our group achieved the highest
GSK-3α selectivity reported so far but suffered from insufficient
aqueous solubility. This work presents the solubility-driven optimization
of our isoform-selective inhibitors using a scorpion shaped lead.
Among 15 novel compounds, compound 27 showed high activity
against GSK-3α/β with the highest GSK-3α selectivity
reported to date. Compound 27 was profiled for bioavailability
and toxicity in a zebrafish embryo phenotype assay. Selective GSK-3α
targeting in AML cell lines was achieved with compound 27, resulting in a strong differentiation phenotype and colony formation
impairment, confirming the potential of GSK-3α inhibition in
AML therapy.