Small-molecule inhibitors of lysine methyltransferases SMYD2 and SMYD3: current trends

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

• 1. Boriack-Sjodin PA, Swinger KK. Protein methyltransferases: a distinct, diverse, and dynamic family of enzymes. Biochemistry 55(11), 1557–1569 (2016).
  Medline CASGoogle Scholar
• 2. Copeland RA, Solomon ME, Richon VM. Protein methyltransferases as a target class for drug discovery. Nat. Rev. Drug Discov. 8(9), 724–732 (2009).
  Medline CASGoogle Scholar
• 3. Copeland RA. Molecular pathways: protein methyltransferases in cancer. Clin. Cancer Res. 19(23), 6344–6350 (2013).
  Medline CASGoogle Scholar
• 4. Hamamoto R, Saloura V, Nakamura Y. Critical roles of non-histone protein lysine methylation in human tumorigenesis. Nat. Rev. Cancer. 15(2), 110–124 (2015).
  Medline CASGoogle Scholar
• 5. Copeland RA. Protein methyltransferase inhibitors as precision cancer therapeutics: a decade of discovery. Philos. Trans. R. Soc. B Biol. Sci. 373(1748), pii:20170080 (2018). •• Exhaustive review on methyltransferase enzymes as therapeutics targets in targeted cancer therapy.
  MedlineGoogle Scholar
• 6. Copeland RA. Epigenetic medicinal chemistry. ACS Med. Chem. Lett. 7(2), 124–127 (2016).
  Medline CASGoogle Scholar
• 7. Leinhart K, Brown M. SET/MYND lysine methyltransferases regulate gene transcription and protein activity. Genes (Basel) 2(1), 210–218 (2011).
  Medline CASGoogle Scholar
• 8. Spellmon N, Holcomb J, Trescott L, Sirinupong N, Yang Z. Structure and function of SET and MYND domain-containing proteins. Int. J. Mol. Sci. 16(1), 1406–1408 (2015).
  Medline CASGoogle Scholar
• 9. Komatsu S, Imoto I, Tsuda H et al.Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous cell carcinoma. Carcinogenesis 30(7), 1139–1146 (2009).
  Medline CASGoogle Scholar
• 10. Cho H-S, Hayami S, Toyokawa G et al.RB1 methylation by SMYD2 enhances cell cycle progression through an increase of RB1 phosphorylation. Neoplasia 14(6), 476–478 (2012).
  Medline CASGoogle Scholar
• 11. Reynoird N, Mazur PK, Stellfeld T et al.Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer. Genes Dev. 30(7), 772–785 (2016).
  Medline CASGoogle Scholar
• 12. Li LX, Zhou JX, Calvet JP, Godwin AK, Jensen RA, Li X. Lysine methyltransferase SMYD2 promotes triple negative breast cancer progression. Cell Death Dis. 9(3), 326 (2018).
  Google Scholar
• 13. Cock-Rada AM, Medjkane S, Janski N et al.SMYD3 promotes cancer invasion by epigenetic upregulation of the metalloproteinase MMP-9. Cancer Res. 72(3), 810–820 (2012).
  Medline CASGoogle Scholar
• 14. Hamamoto R, Furukawa Y, Morita M et al.SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat. Cell Biol. 6(8), 731–740 (2004).
  Medline CASGoogle Scholar
• 15. Dong SW, Zhang H, Wang BL, Sun P, Wang YG, Zhang P. Effect of the downregulation of SMYD3 expression by RNAi on RIZ1 expression and proliferation of esophageal squamous cell carcinoma. Oncol. Rep. 32(3), 1064–1070 (2014).
  Medline CASGoogle Scholar
• 16. Wang L, Wang Q-T, Liu Y-P et al.ATM signaling pathway is implicated in the SMYD3-mediated proliferation and migration of gastric cancer cells. J. Gastric Cancer 17(4), 295 (2017).
  MedlineGoogle Scholar
• 17. McGrath J, Trojer P. Targeting histone lysine methylation in cancer. Pharmacol. Ther. 150, 1–22 (2015).
  Medline CASGoogle Scholar
• 18. Rajajeyabalachandran G, Kumar S, Murugesan T et al.Therapeutical potential of deregulated lysine methyltransferase SMYD3 as a safe target for novel anticancer agents. Expert Opin. Ther. Targets 21(2), 145–157 (2017).
  Medline CASGoogle Scholar
• 19. Copeland RA, Moyer MP, Richon VM. Targeting genetic alterations in protein methyltransferases for personalized cancer therapeutics. Oncogene 32(8), 939–946 (2013).
  Medline CASGoogle Scholar
• 20. Thomenius MJ, 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 13(6), e0197372 (2018). •• The work presents the most potent inhibitors of either SMYD2 or SMYD3 so-far discovered.
  MedlineGoogle Scholar
• 21. Sarris ME, Moulos P, Haroniti A, Giakountis A, Talianidis I. Smyd3 is a transcriptional potentiator of multiple cancer-promoting genes and required for liver and colon cancer development. Cancer Cell 29(3), 354–366 (2016).
  Medline CASGoogle Scholar
• 22. Abu-Farha M, Lambert J-P, Al-Madhoun AS, Elisma F, Skerjanc IS, Figeys D. The tale of two domains. Mol. Cell. Proteomics 7(3), 560–572 (2008).
  Medline CASGoogle Scholar
• 23. Spellmon N, Sun X, Sirinupong N, Edwards B, Li C, Yang Z. Molecular dynamics simulation reveals correlated inter-lobe motion in protein lysine methyltransferase SMYD2. PLoS ONE 10(12), 1–10 (2015).
  Google Scholar
• 24. Herz HM, Garruss A, Shilatifard A. SET for life: biochemical activities and biological functions of SET domain-containing proteins. Trends Biochem. Sci. 38(12), 621–639 (2013).
  Medline CASGoogle Scholar
• 25. Gamsjaeger R, Liew CK, Loughlin FE, Crossley M, Mackay JP. Sticky fingers: zinc-fingers as protein-recognition motifs. Trends Biochem. Sci. 32(2), 63–70 (2007).
  Medline CASGoogle Scholar
• 26. Blatch GL, Lässle M. The tetratricopeptide repeat: a structural motif mediating protein-protein interactions. BioEssays 21(11), 932–939 (1999).
  Medline CASGoogle Scholar
• 27. Cowen SD, Russell D, Dakin LA et al.Design, synthesis, and biological activity of substrate competitive SMYD2 inhibitors. J. Med. Chem. 59(24), 11079–11097 (2016).
  Medline CASGoogle Scholar
• 28. 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. 291(17), 9173–9180 (2016). • A key study on structural requirement for substrate preference.
  Medline CASGoogle Scholar
• 29. Huang J, Perez-Burgos L, Placek BJ et al.Repression of p53 activity by Smyd2-mediated methylation. Nature 444(7119), 629–632 (2006).
  Medline CASGoogle Scholar
• 30. Saddic LA, West LE, Aslanian A et al.Methylation of the retinoblastoma tumor suppressor by SMYD2. J. Biol. Chem. 285(48), 37733–37740 (2010).
  Medline CASGoogle Scholar
• 31. Jiang Y, Trescott L, Holcomb J et al.Structural insights into estrogen receptor α methylation by histone methyltransferase SMYD2, a cellular event implicated in estrogen signaling regulation. J. Mol. Biol. 426(20), 3413–3425 (2014). • Discloses the crystal structure of SMYD2 in complex with ERα.
  Medline CASGoogle Scholar
• 32. van Aller GS, Reynoird N, Barbash O et al.Smyd3 regulates cancer cell phenotypes and catalyzes histone H4 lysine 5 methylation. Epigenetics 7(4), 340–343 (2012).
  Medline CASGoogle Scholar
• 33. Yoshioka Y, Suzuki T, Matsuo Y et al.SMYD3-mediated lysine methylation in the PH domain is critical for activation of AKT1. Oncotarget 7, 75023–75037 (2016).
  MedlineGoogle Scholar
• 34. Mazur PK, Reynoird N, Khatri P et al.SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature 510(7504), 283–287 (2014).
  Medline CASGoogle Scholar
• 35. Kunizaki M, Hamamoto R, Silva FP et al.The lysine 831 of vascular endothelial growth factor receptor 1 is a novel target of methylation by SMYD3. Cancer Res. 67(22), 10759–10765 (2007).
  Medline CASGoogle Scholar
• 36. Foreman KW, Brown M, Park F et al.Structural and functional profiling of the human histone methyltransferase SMYD3. PLoS ONE 6(7), e22290 (2011).
  MedlineGoogle Scholar
• 37. Ferguson AD, Larsen NA, Howard T et al.Structural basis of substrate methylation and inhibition of SMYD2. Structure 19(9), 1262–1273 (2011). • Discloses the first crystal structure of SMYD2 in complex with the first identified inhibitor.
  Medline CASGoogle Scholar
• 38. Wang L, Li N, Zhang H et al.Structure of human SMYD2 protein reveals the basis of p53 tumor suppressor methylation. J. Biol. Chem. 286(44), 38725–38737 (2011).
  Medline CASGoogle Scholar
• 39. Chandramouli B, Silvestri V, Scarno M, Ottini L, Chillemi G. Smyd3 open & closed lock mechanism for substrate recruitment: the hinge motion of C-terminal domain inferred from μ-second molecular dynamics simulations. Biochim. Biophys. Acta 1860(7), 1466–1474 (2016).
  Medline CASGoogle Scholar
• 40. Chandramouli B, Chillemi G. Conformational dynamics of lysine methyltransferase Smyd2. Insights into the different substrate crevice characteristics of SMYD2 and SMYD3. J. Chem. Inf. Model. 56(12), 2467–2475 (2016).
  Medline CASGoogle Scholar
• 41. Sirinupong N, Brunzelle J, Doko E, Yang Z. Structural insights into the autoinhibition and posttranslational activation of histone methyltransferase SmyD3. J. Mol. Biol. 406(1), 149–159 (2011).
  Medline CASGoogle Scholar
• 42. Brown MA, Foreman K, Harriss J et al.C-terminal domain of SMYD3 serves as a unique HSP90-regulated motif in oncogenesis. Oncotarget 6(6), 4005–4019 (2015).
  MedlineGoogle Scholar
• 43. Nguyen H, Allali-Hassani A, Antonysamy S et al.LLY-507, a cell-active, potent, and selective inhibitor of protein-lysine methyltransferase SMYD2. J. Biol. Chem. 290(22), 13641–13653 (2015).
  Medline CASGoogle Scholar
• 44. Sweis RF, Wang Z, Algire M et al.Discovery of A-893, a new cell-active benzoxazinone inhibitor of lysine methyltransferase SMYD2. ACS Med. Chem. Lett. 6, 695–700 (2015). • Reports on an extensive and systematic structure–activity relationship study on structural features for SMYD2 inhibition starting from AZ505 scaffold.
  Medline CASGoogle Scholar
• 45. Eggert E, Hillig RC, 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. 59(10), 4578–4600 (2016).
  Medline CASGoogle Scholar
• 46. Fabian MA, Biggs WH, Treiber DK et al.A small molecule-kinase interaction map for clinical kinase inhibitors. Nat. Biotechnol. 23(3), 329–336 (2005).
  Medline CASGoogle Scholar
• 47. Peserico A, Germani A, Sanese P et al.A SMYD3 small-molecule inhibitor impairing cancer cell growth. J. Cell. Physiol. 230(10), 2447–2460 (2015).
  Medline CASGoogle Scholar
• 48. Del Rio A, Barbosa AJM, Caporuscio F, Mangiatordi GF. CoCoCo: a free suite of multiconformational chemical databases for high-throughput virtual screening purposes. Mol. Biosyst. 6(11), 2122–2128 (2010).
  MedlineGoogle Scholar
• 49. Giannetti AM. From eperimental design to validated hits: a comprehensive walk-through of fragment lead identification using surface plasmon resonance. Methods Enzymol. 493, 169–218 (2011).
  Medline CASGoogle Scholar
• 50. Van Aller GS, Graves AP, Elkins PA et al.Structure-based design of a novel SMYD3 inhibitor that bridges the SAM-and MEKK2-binding pockets. Structure 24(5), 774–781 (2016).
  Medline CASGoogle Scholar
• 51. Yu W, Smil D, Li F et al.Bromo-deaza-SAH: a potent and selective DOT1L inhibitor. Bioorganic Med. Chem. 21(7), 1787–1794 (2013).
  Medline CASGoogle Scholar
• 52. Basavapathruni A, Jin L, Daigle SR et al.Conformational adaptation drives potent, selective and durable inhibition of the human protein methyltransferase DOT1L. Chem. Biol. Drug Des. 80(6), 971–980 (2012).
  Medline CASGoogle Scholar
• 53. Mitchell LH, Boriack-Sjodin PA, Smith S et al.Novel oxindole sulfonamides and sulfamides: EPZ031686, the first orally bioavailable small molecule SMYD3 inhibitor. ACS Med. Chem. Lett. 7(2), 134–138 (2016). • Discloses the first crystal structure an inhibitor targeting the substrate-binding site of SMYD3.
  Medline CASGoogle Scholar
• 54. Jafari R, Almqvist H, Axelsson H et al.The cellular thermal shift assay for evaluating drug target interactions in cells. Nat. Protoc. 9(9), 2100–2122 (2014).
  Medline CASGoogle Scholar
• 55. Structural Genomics Consortium BAY-6035 A potent, peptide-competitive chemical probe for SMYD3 https://www.thesgc.org/chemical-probes/BAY-6035
  Google Scholar
• 56. Andreoli F, Barbosa AJM, Parenti MD, Del Rio A. Modulation of epigenetic targets for anticancer therapy: clinicopathological relevance, structural data and drug discovery perspectives. Curr. Pharm. Des. 19(4), 578–613 (2012).
  Google Scholar
• 57. Andreoli F, Del Rio A. Computer-aided molecular design of compounds targeting histone modifying enzymes. Comput. Struct. Biotechnol. J. 13, 358–365 (2015).
  Medline CASGoogle Scholar
• 58. Fenizia C, Bottino C, Corbetta S et al.SMYD3 promotes the epithelial-mesenchymal transition in breast cancer. Nucleic Acids Res. 1221 (2018) (In Press).
  Google Scholar