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Open AccessArticle

In Silico/In Vitro Hit-to-Lead Methodology Yields SMYD3 Inhibitor That Eliminates Unrestrained Proliferation of Breast Carcinoma Cells

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Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO 80523-1005, USA
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Department of Biology, University of Tabuk, Tabuk 47713, Saudi Arabia
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Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO 80045-7109, USA
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Department of Chemistry, Colorado State University, Fort Collins, CO 80523-1872, USA
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Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523-1617, USA
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Department of Medical Biochemistry, Zagazig University, Zagazig 44511, Egypt
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Department of Environmental & Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523-1618, USA
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Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80523-1678, USA
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Epidemiology Section, Colorado School of Public Health, Fort Collins, CO 80523-1612, USA
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Institute for Learning and Teaching, Colorado State University, Fort Collins, CO 80523-1052, USA
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Department of Ethnic Studies, Colorado State University, Fort Collins, CO 80523-1790, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(24), 9549; https://doi.org/10.3390/ijms21249549
Received: 30 October 2020 / Revised: 10 December 2020 / Accepted: 11 December 2020 / Published: 15 December 2020
(This article belongs to the Special Issue Drug Discovery and Development 2.0)
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. View Full-Text
Keywords: hit-to-lead; in silico drug development; SMYD3; methyltransferase; Inhibitor-4; breast cancer; cell proliferation; cell cycle; apoptosis hit-to-lead; in silico drug development; SMYD3; methyltransferase; Inhibitor-4; breast cancer; cell proliferation; cell cycle; apoptosis
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MDPI and ACS Style

Alshiraihi, I.M.; Jarrell, D.K.; Arhouma, Z.; Hassell, K.N.; Montgomery, J.; Padilla, A.; Ibrahim, H.M.; Crans, D.C.; Kato, T.A.; Brown, M.A. In Silico/In Vitro Hit-to-Lead Methodology Yields SMYD3 Inhibitor That Eliminates Unrestrained Proliferation of Breast Carcinoma Cells. Int. J. Mol. Sci. 2020, 21, 9549. https://doi.org/10.3390/ijms21249549

AMA Style

Alshiraihi IM, Jarrell DK, Arhouma Z, Hassell KN, Montgomery J, Padilla A, Ibrahim HM, Crans DC, Kato TA, Brown MA. In Silico/In Vitro Hit-to-Lead Methodology Yields SMYD3 Inhibitor That Eliminates Unrestrained Proliferation of Breast Carcinoma Cells. International Journal of Molecular Sciences. 2020; 21(24):9549. https://doi.org/10.3390/ijms21249549

Chicago/Turabian Style

Alshiraihi, Ilham M.; Jarrell, Dillon K.; Arhouma, Zeyad; Hassell, Kelly N.; Montgomery, Jaelyn; Padilla, Alyssa; Ibrahim, Hend M.; Crans, Debbie C.; Kato, Takamitsu A.; Brown, Mark A. 2020. "In Silico/In Vitro Hit-to-Lead Methodology Yields SMYD3 Inhibitor That Eliminates Unrestrained Proliferation of Breast Carcinoma Cells" Int. J. Mol. Sci. 21, no. 24: 9549. https://doi.org/10.3390/ijms21249549

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