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.
Clemens Schöpf Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt , 64287 Darmstadt, Germany.
Theresa
T
Neumann
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School , Boston, Massachusetts 02215, United States.
Lina
L
Benajiba
Clemens Schöpf Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt , 64287 Darmstadt, Germany.
Stefan
S
Göring
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School , Boston, Massachusetts 02215, United States.
Kimberly
K
Stegmaier
Clemens Schöpf Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt , 64287 Darmstadt, Germany.
Boris
B
Schmidt
D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000071679:Glycogen Synthase Kinase 3 beta; D018922:HL-60 Cells; D006801:Humans; D007527:Isoenzymes; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008958:Models, Molecular; D008968:Molecular Conformation; D012995:Solubility; D013329:Structure-Activity Relationship; D014410:Tumor Stem Cell Assay; D015027:Zebrafish
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha