Work

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

Year: 2015

Type: article

Abstract: 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.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.5b01200

Authors: Theresa Neumann, Lina Benajiba, Stefan Göring, Kimberly Stegmaier, Boris Schmidt

Institutions: Technische Universität Darmstadt, Harvard University, Dana-Farber Cancer Institute

Language: English

Topic: Heterocyclic Compound Synthesis and Bioactivity

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

SDG: Good health and well-being

Open Access status: green

Funders: Leukemia and Lymphoma Society, Hans und Ilse Breuer-Stiftung, National Cancer Institute