Discovery of a Non-Nucleoside SETD2 Methyltransferase Inhibitor against Acute Myeloid Leukemia

Dávid Bajusz,György M Keserű,Florian Grebien,Zsolt Bognár,Jessica Ebner

doi:10.3390/ijms221810055

Abstract

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.

Highlights

In eukaryotic cells, histone proteins play instrumental roles in the packaging of DNA inside the nucleus
SET domain containing 2 (SETD2) inhibitors,we weset setout outtotoconduct conducta astructurestrucTo identify the new chemotypes of SETD2 inhibitors, ture-based virtual screening campaign on the
We did not have access to further methyltransferase assays, we examined this possibility by a brief docking study against the available PDB structures of 15 other methyltransferases (Supplementary Materials, Section S7)

Summary

Introduction

Histone proteins play instrumental roles in the packaging of DNA inside the nucleus. The four major histones (H2a, H2b, H3, and H4) form a disc-shaped octameric complex, providing a structural framework for binding of the DNA double helix to form chromatin [1]. In addition to this role, the side chains of histone proteins are subject to highly specific post-translational modifications, including methylation, acetylation, and others. SET domain containing 2 (SETD2) is the only known lysine methyltransferase (KMT)

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