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In Silico/In Vitro Hit-to-Lead Methodology Yields SMYD3 Inhibitor That Eliminates Unrestrained Proliferation of
Ilham M Alshiraihi1,2, Dillon K Jarrell3, Zeyad Arhouma1,4
1Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO 80523-1005, USA.
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.
Insights
Researchers identified a novel small molecule inhibitor targeting SMYD3 (a key protein in cancer cell growth). This inhibitor effectively halts cancer cell proliferation and offers a promising new avenue for cancer treatment development.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- SMYD3, a lysine methyltransferase, drives uncontrolled proliferation in breast, colorectal, and hepatocellular carcinomas by regulating over 80 genes.
- Targeting SMYD3 presents a promising strategy for developing novel cancer therapeutics.
Purpose of the Study:
- To validate an in silico/in vitro platform for developing enzyme inhibitors.
- To identify a lead small molecule candidate for inhibiting SMYD3.
Main Methods:
- Utilized Schrodinger® software for in silico screening of small molecule libraries.
- Assessed top five predicted compounds in vitro using direct binding assays and breast cancer cell lines.
Main Results:
- Identified Inhibitor-4 as a potent SMYD3 inhibitor.
- Inhibitor-4 restored normal cell proliferation rates, induced cell cycle arrest, and promoted apoptosis in cancer cells.
- Demonstrated no adverse effects on wildtype cells.
Conclusions:
- Validated a rapid and cost-effective small molecule hit-to-lead methodology.
- Inhibitor-4 is a promising candidate for SMYD3-targeted cancer therapy.
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