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Type of publication: Journal Article
Type of document: Full Paper

Year: 2021

Authors: Bajusz, D; Bognár, Z; Ebner, J; Grebien, F; Keserű, GM

Title: Discovery of a non-nucleoside setd2 methyltransferase inhibitor against acute myeloid leukemia.

Source: Int J Mol Sci. 2021; 22(18):10055

Authors Vetmeduni Vienna:

Ebner Jessica
Grebien Florian

Vetmed Research Units
Institute for Medical Biochemistry

Project(s): Common Oncogenic Mechanisms in Multi-Partner Translocation Families in Acute Myeloid Leukemia

Histone methyltransferases (HMTs) have attracted considerable attention as potential targets for pharmaceutical intervention in various malignant diseases. These enzymes are known for introducing methyl marks at specific locations of histone proteins, creating a complex system that regulates epigenetic control of gene expression and cell differentiation. Here, we describe the identification of first-generation cell-permeable non-nucleoside type inhibitors of SETD2, the only mammalian HMT that is able to tri-methylate the K36 residue of histone H3. By generating the epigenetic mark H3K36me3, SETD2 is involved in the progression of acute myeloid leukemia. We developed a structure-based virtual screening protocol that was first validated in retrospective studies. Next, prospective screening was performed on a large library of commercially available compounds. Experimental validation of 22 virtual hits led to the discovery of three compounds that showed dose-dependent inhibition of the enzymatic activity of SETD2. Compound C13 effectively blocked the proliferation of two acute myeloid leukemia (AML) cell lines with MLL rearrangements and led to decreased H3K36me3 levels, prioritizing this chemotype as a viable chemical starting point for drug discovery projects.

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