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

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.

Maximizing the integration of virtual and experimental screening in hit discovery

“…Our recent work on SETD2 inhibitors nicely illustrates the concept [51]. SETD2 is a histone methyltransferase that was recently established as a new oncotarget, primarily against certain types of leukemia [128,129].…”

“…Screening the leadlike subset of the ZINC15 database (235 million compounds [49]) has resulted in the identification of potent, noncovalent inhibitors of the SARS-CoV-2 main protease [50]. It is worth to note that ligand-and structure-based virtual approaches (such as docking, shape screening and pharmacophore screening) can be flexibly combined to result in stepwise [51] or parallel [52] virtual screening workflows, although to our knowledge this is not yet widespread in ultra-large screens. We should note that consensus screening strategies can also be realized on the level of considering multiple scoring functions in docking-based virtual screening workflows [53,54].…”

Recent advances in prostate cancer: WNT signaling, chromatin regulation, and transcriptional coregulators

“…These results indicate that expression regulation or enzymatic inhibition of SETD2 is potential drug targets for prostate cancer. SETD2-selective inhibitors (EPZ-719, 95 compound C13, 96 and EZM0414 97 ) have been reported. Among them, compound C13 inhibits the proliferation of leukemia cell lines 96 and EZM0414 inhibits the proliferation of multiple myeloma cells in xenograft model mice.…”

“…SETD2-selective inhibitors (EPZ-719, 95 compound C13, 96 and EZM0414 97 ) have been reported. Among them, compound C13 inhibits the proliferation of leukemia cell lines 96 and EZM0414 inhibits the proliferation of multiple myeloma cells in xenograft model mice. 97 Thus, these compounds may be a useful drug for prostate cancer, although EZH2 expression levels may be altered.…”

Structure-Aided Design, Synthesis, and Biological Evaluation of Potent and Selective Non-Nucleoside Inhibitors Targeting Protein Arginine Methyltransferase 5

“…The discovery of potent and selective non-nucleoside PRMT5 inhibitors holds great promise to improve drug-like properties via attenuation of the polarity and poor membrane permeability associated with the known nucleoside inhibitors − and is of particular significance. In this regard, we performed a structure-aided drug design approach to facilitate the discovery of highly potent and selective non-nucleoside PRMT5 inhibitors.…”