Discovery of the SMYD3 Inhibitor BAY-6035 Using Thermal Shift Assay (TSA)-Based High-Throughput Screening

1. Spellmon, N., Holcomb, J., Trescott, L., et al. Structure and Function of SET and MYND Domain-Containing Proteins. Int. J. Mol. Sci. 2015, 16, 1406–1428.
Google Scholar | Crossref | Medline2. Hamamoto, R., Furukawa, Y., Morita, M., et al. SMYD3 Encodes a Histone Methyltransferase Involved in the Proliferation of Cancer Cells. Nat. Cell Biol. 2004, 6, 731–740.
Google Scholar | Crossref | Medline3. He, C., Xu, J., Zhang, J., et al. High Expression of Trimethylated Histone H3 Lysine 4 Is Associated with Poor Prognosis in Hepatocellular Carcinoma. Hum. Pathol. 2012, 43, 1425–1435.
Google Scholar | Crossref | Medline4. Sarris, M. E., Moulos, P., Haroniti, A., et al. Smyd3 Is a Transcriptional Potentiator of Multiple Cancer-Promoting Genes and Required for Liver and Colon Cancer Development. Cancer Cell 2016, 29, 354–366.
Google Scholar | Crossref | Medline5. Zhu, Y., Zhu, M. X., Zhang, X. D., et al. SMYD3 Stimulates EZR and LOXL2 Transcription to Enhance Proliferation, Migration, and Invasion in Esophageal Squamous Cell Carcinoma. Hum. Pathol. 2016, 52, 153–163.
Google Scholar | Crossref | Medline6. Liu, Y., Deng, J., Luo, X., et al. Overexpression of SMYD3 Was Associated with Increased STAT3 Activation in Gastric Cancer. Med Oncol. 2015, 32, 404.
Google Scholar | Crossref | Medline7. Liu, Y., Liu, H., Luo, X., et al. Overexpression of SMYD3 and Matrix Metalloproteinase-9 Are Associated with Poor Prognosis of Patients with Gastric Cancer. Tumour Biol. 2015, 36, 4377–4386.
Google Scholar | Crossref | Medline8. Wang, H., Liu, Y., Tan, W., et al. Association of the Variable Number of Tandem Repeats Polymorphism in the Promoter Region of the SMYD3 Gene with Risk of Esophageal Squamous Cell Carcinoma in Relation to Tobacco Smoking. Cancer Sci. 2008, 99, 787–791.
Google Scholar | Crossref | Medline9. Mazur, P. K., Reynoird, N., Khatri, P., et al. SMYD3 Links Lysine Methylation of MAP3K2 to Ras-Driven Cancer. Nature 2014, 510, 283–287.
Google Scholar | Crossref | Medline10. Gaedcke, J., Grade, M., Jung, K., et al. Mutated KRAS Results in Overexpression of DUSP4, a MAP-Kinase Phosphatase, and SMYD3, a Histone Methyltransferase, in Rectal Carcinomas. Genes Chromosomes Cancer 2010, 49, 1024–1034.
Google Scholar | Crossref | Medline11. Watanabe, T., Kobunai, T., Yamamoto, Y., et al. Differential Gene Expression Signatures between Colorectal Cancers with and without KRAS Mutations: Crosstalk between the KRAS Pathway and Other Signalling Pathways. Eur. J. Cancer 2011, 47, 1946–1954.
Google Scholar | Crossref | Medline12. Hamamoto, R., Silva, F. P., Tsuge, M., et al. Enhanced SMYD3 Expression Is Essential for the Growth of Breast Cancer Cells. Cancer Sci. 2006, 97, 113–118.
Google Scholar | Crossref | Medline13. Zeng, B., Li, Z., Chen, R., et al. Epigenetic Regulation of miR-124 by Hepatitis C Virus Core Protein Promotes Migration and Invasion of Intrahepatic Cholangiocarcinoma Cells by Targeting SMYD3. FEBS Lett. 2012, 586, 3271–3278.
Google Scholar | Crossref | Medline14. Zou, J. N., Wang, S. Z., Yang, J. S., et al. Knockdown of SMYD3 by RNA Interference Down-Regulates c-Met Expression and Inhibits Cells Migration and Invasion Induced by HGF. Cancer Lett. 2009, 280, 78–85.
Google Scholar | Crossref | Medline15. Cock-Rada, A. M., Medjkane, S., Janski, N., et al. SMYD3 promotes cancer Invasion by Epigenetic Upregulation of the Metalloproteinase MMP-9. Cancer Res. 2012, 72, 810–820.
Google Scholar | Crossref | Medline16. Chen, D., Liu, L., Luo, X., et al. Effect of SMYD3 on the microRNA Expression Profile of MCF-7 Breast Cancer Cells. Oncol. Lett. 2017, 14, 1831–1840.
Google Scholar | Crossref | Medline17. Chen, L. B., Xu, J. Y., Yang, Z., et al. Silencing SMYD3 in Hepatoma Demethylates RIZI Promoter Induces Apoptosis and Inhibits Cell Proliferation and Migration. World J. Gastroenterol. 2007, 13, 5718–5724.
Google Scholar | Crossref | Medline18. Liu, C., Wang, C., Wang, K., et al. SMYD3 as an Oncogenic Driver in Prostate Cancer by Stimulation of Androgen Receptor Transcription. J. Natl. Cancer Inst. 2013, 105, 1719–1728.
Google Scholar | Crossref | Medline19. Liu, C., Fang, X., Ge, Z., et al. The Telomerase Reverse Transcriptase (hTERT) Gene Is a Direct Target of the Histone Methyltransferase SMYD3. Cancer Res. 2007, 67, 2626–2631.
Google Scholar | Crossref | Medline20. Luo, X. G., Zhang, C. L., Zhao, W. W., et al. Histone Methyltransferase SMYD3 Promotes MRTF-A-Mediated Transactivation of MYL9 and Migration of MCF-7 Breast Cancer Cells. Cancer Lett. 2014, 344, 129–137.
Google Scholar | Crossref | Medline21. Van Aller, G. S., Reynoird, N., Barbash, O., et al. Smyd3 Regulates Cancer Cell Phenotypes and Catalyzes Histone H4 Lysine 5 Methylation. Epigenetics 2012, 7, 340–343.
Google Scholar | Crossref | Medline22. Kunizaki, M., Hamamoto, R., Silva, F. P., et al. The Lysine 831 of Vascular Endothelial Growth Factor Receptor 1 Is a Novel Target of Methylation by SMYD3. Cancer Res. 2007, 67, 10759–10765.
Google Scholar | Crossref | Medline23. Brown, M. A., Foreman, K., Harriss, J., et al. C-Terminal Domain of SMYD3 Serves as a Unique HSP90-Regulated Motif in Oncogenesis. Oncotarget 2015, 6, 4005–4019.
Google Scholar | Crossref | Medline24. Donlin, L. T., Andresen, C., Just, S., et al. Smyd2 Controls Cytoplasmic Lysine Methylation of Hsp90 and Myofilament Organization. Genes Dev. 2012, 26, 114–119.
Google Scholar | Crossref | Medline25. Ying, H., DePinho, R. A. Cancer Signaling: When Phosphorylation Meets Methylation. Cell Res. 2014, 24, 1282–1283.
Google Scholar | Crossref | Medline26. Fu, W., Liu, N., Qiao, Q., et al. Structural Basis for Substrate Preference of SMYD3, a SET Domain-Containing Protein Lysine Methyltransferase. J. Biol. Chem. 2016, 291, 9173–9180.
Google Scholar | Crossref | Medline27. Yoshioka, Y., Suzuki, T., Matsuo, Y., et al. SMYD3-Mediated Lysine Methylation in the PH Domain Is Critical for Activation of AKT1. Oncotarget 2016, 7, 75023–75037.
Google Scholar | Crossref | Medline28. Yoshioka, Y., Suzuki, T., Matsuo, Y., et al. Protein Lysine Methyltransferase SMYD3 Is Involved in Tumorigenesis through Regulation of HER2 Homodimerization. Cancer Med. 2017, 6, 1665–1672.
Google Scholar | Crossref | Medline29. Fabini, E., Manoni, E., Ferroni, C., et al. Small-Molecule Inhibitors of Lysine Methyltransferases SMYD2 and SMYD3: Current Trends. Future Med. Chem. 2019, 11, 901–921.
Google Scholar | Crossref | Medline30. Peserico, A., Germani, A., Sanese, P., et al. A SMYD3 Small-Molecule Inhibitor Impairing Cancer Cell Growth. J. Cell. Physiol. 2015, 230, 2447–2460.
Google Scholar | Crossref | Medline31. Van Aller, G. S., Graves, A. P., Elkins, P. A., et al. Structure-Based Design of a Novel SMYD3 Inhibitor That Bridges the SAM-and MEKK2-Binding Pockets. Structure 2016, 24, 774–781.
Google Scholar | Crossref | Medline32. Mitchell, L. H., Boriack-Sjodin, P. A., Smith, S., et al. Novel Oxindole Sulfonamides and Sulfamides: EPZ031686, the First Orally Bioavailable Small Molecule SMYD3 Inhibitor. ACS Med. Chem. Lett. 2016, 7, 134–138.
Google Scholar | Crossref | Medline33. Thomenius, M. J., Totman, J., Harvey, D., et al. Small Molecule Inhibitors and CRISPR/Cas9 Mutagenesis Demonstrate That SMYD2 and SMYD3 Activity Are Dispensable for Autonomous Cancer Cell Proliferation. PloS One 2018, 13, e0197372.
Google Scholar | Crossref | Medline34. Huang, C., Liew, S. S., Lin, G. R., et al. Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3. ACS Med. Chem. Lett. 2019, 10, 978–984.
Google Scholar | Crossref | Medline35. Gradl, S., Steuber, H., Weiske, J., et al. Abstract 1646: Discovery and Characterization of BAY-6035, a Novel Benzodiazepine-Based SMYD3 Inhibitor. Cancer Res. 2018, 78, 1646.
Google Scholar36. Arrowsmith, C. H., Audia, J. E., Austin, C., et al. The Promise and Peril of Chemical Probes. Nat. Chem. Biol. 2015, 11, 536–541.
Google Scholar | Crossref | Medline37. Bunnage, M. E., Chekler, E. L., Jones, L. H. Target Validation Using Chemical Probes. Nat. Chem. Biol. 2013, 9, 195–199.
Google Scholar | Crossref | Medline38. Scheer, S., Ackloo, S., Medina, T. S., et al. A Chemical Biology Toolbox to Study Protein Methyltransferases and Epigenetic Signaling. Nat. Commun. 2019, 10, 19.
Google Scholar | Crossref | Medline39. Ried, W., Urlass, G. Über heterocyclische Siebenringsysteme, I. Mitteil.: Das 7-Methyl-2.3-benzo-1.4-diaza-cyclohepten-(2)-on-(5) und seine Derivate. Chemische Berichte 1953, 86, 1101–1106.
Google Scholar | Crossref40. Hashiyama, T., Inoue, H., Takeda, M., et al. Reactions of 3-Phenylglycidic Esters. V. Reaction of Methyl 3-(4-Methoxyphenyl) Glycidate with 2-Nitroaniline and Synthesis of 1,5-Benzodiazepine Derivatives. Chem. Pharm. Bull. 1985, 33, 2348–2358.
Google Scholar | Crossref41. Fang, C., Cao, J., Sun, K., et al. Direct and Enantioselective Synthesis of N–H-Free 1,5-Benzodiazepin-2-ones by an N-Heterocyclic Carbene Catalyzed [3+4] Annulation Reaction. Chemistry 2018, 24, 2103–2108.
Google Scholar | Crossref | Medline42. Borrmann, R., Koenigs, R. M., Zoller, J., et al. Asymmetric Hydrogenation of Cyclic Imines and Enamines: Access to 1,5-Benzodiazepine Pharmacophores. Synthesis 2017, 49, 310–318.
Google Scholar43. Stresemann, C., Rohn, U., Steuber, H., et al. 4-Oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-7-carboxamides. WO/2019/034532, February 21, 2019.
Google Scholar44. Eggert, E., Hillig, R. C., Koehr, S., et al. Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based In Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2. J. Med. Chem. 2016, 59, 4578–4600.
Google Scholar | Crossref | Medline45. Bauer, M. R., Jones, R. N., Baud, M. G., et al. Harnessing Fluorine-Sulfur Contacts and Multipolar Interactions for the Design of p53 Mutant Y220C Rescue Drugs. ACS Chem. Biol. 2016, 11, 2265–2274.
Google Scholar | Crossref | Medline46. Abad-Zapatero, C., Metz, J. T. Ligand Efficiency Indices as Guideposts for Drug Discovery. Drug Discov. Today 2005, 10, 464–469.
Google Scholar | Crossref | Medline47. Pantoliano, M. W., Petrella, E. C., Kwasnoski, J. D., et al. High-Density Miniaturized Thermal Shift Assays as a General Strategy for Drug Discovery. J. Biomol. Screen. 2001, 6, 429–440.
Google Scholar | SAGE Journals48. Mariaule, V., Dupeux, F., Marquez, J. A. Estimation of Crystallization Likelihood through a Fluorimetric Thermal Stability Assay. Methods Mol. Biol. 2014, 1091, 189–195.
Google Scholar | Crossref | Medline

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