Abstract
SMYD3 is a lysine methyltransferase that regulates the expression of over 80 genes and is required for the uncontrolled proliferation of most breast, colorectal, and hepatocellular carcinomas. The elimination of SMYD3 restores normal expression patterns of these genes and halts aberrant cell proliferation, making it a promising target for small molecule inhibition. In this study, we sought to establish a proof of concept for our in silico/in vitro hit-to-lead enzyme inhibitor development platform and to identify a lead small molecule candidate for SMYD3 inhibition. We used Schrodinger® software to screen libraries of small molecules in silico and the five compounds with the greatest predicted binding affinity within the SMYD3 binding pocket were purchased and assessed in vitro in direct binding assays and in breast cancer cell lines. We have confirmed the ability of one of these inhibitors, Inhibitor-4, to restore normal rates of cell proliferation, arrest the cell cycle, and induce apoptosis in breast cancer cells without affecting wildtype cell behavior. Our results provide a proof of concept for this fast and affordable small molecule hit-to-lead methodology as well as a promising candidate small molecule SMYD3 inhibitor for the treatment of human cancer.
Highlights
SMYD (SET and MYND domain-containing) protein family members constitute a class of methyltransferases that regulate a wide range of normal cellular processes [1,2,3] and are involved in several tumorigenic pathways [3,4,5]
Inhibitor-4 and BCl-121 are Stable in d6-dimethyl sulfoxide (DMSO) Solution Because of the limited solubility of selected molecules in aqueous solution and in media, we dissolved BCI-121 and Inhibitor-4 in d6-DMSO solution to record and analyze the 1D 1H Nuclear Magnetic Resonance (NMR) spectra of both compounds
The major species attributed to Inhibitor-4 and BCI-121 were observed at time 0 and 24 h, as shown in Figure S1a (BCI-121) and Figure S1b (Inhibitor-4)
Summary
SMYD (SET and MYND domain-containing) protein family members constitute a class of methyltransferases that regulate a wide range of normal cellular processes [1,2,3] and are involved in several tumorigenic pathways [3,4,5]. The growth of breast, hepatocellular, and colorectal carcinoma cell lines have been impaired significantly through SMYD3 knockdown [3,8]. These studies demonstrate that the oncogenic impact of SMYD3 is mediated in part by its histone methylation activity and the resulting impact on the expression of oncogenes. SMYD3 interacts with ER in the ligand binding domain and activates the transcriptional machinery of downstream genes [14]. These studies indicate SMYD3 as a potential therapeutic target for cancer treatment
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