Protein methyltransferases as a target class for drug discovery

Nature Reviews Drug Discovery

Volumn 8, Issue 9, 2009, Pages 724-732

  Copeland, Robert A ^a   Solomon, Michael E ^a   Richon, Victoria M ^a  

^a EPIZYME INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 PHENYLSULFAMOYLCINNAMOHYDROXAMIC ACID; 5 AZA 2' DEOXYCYTIDINE; AZACITIDINE; BELINOSTAT; BIX 01294; CHETOCIN; ENTINOSTAT; ENZYME INHIBITOR; ITF 2357; JNJ 26481585; N (2 AMINOPHENYL) 4 (3 PYRIDINYLMETHOXYCARBONYLAMINOMETHYL)BENZAMIDE; N (2 AMINOPHENYL) 4 [4 (3 PYRIDINYL) 2 PYRIMIDINYLAMINOMETHYL]BENZAMIDE; N BENZYL 1 HETEROARYL 3 (TRIFLUOROMETHYL) 1H PYRAZOLE 5 CARBOXAMIDE; PANOBINOSTAT; PROTEIN METHYLTRANSFERASE; ROMIDEPSIN; S ADENOSYLHOMOCYSTEINE; SINEFUNGIN; SNDX 275; TRANSFERASE INHIBITOR; UNCLASSIFIED DRUG; VORINOSTAT;

ANTINEOPLASTIC ACTIVITY; CLINICAL TRIAL; DRUG EFFICACY; DRUG POTENCY; DRUG STRUCTURE; DRUG TARGETING; ENZYME ACTIVITY; ENZYME INHIBITION; ENZYME SUBSTRATE; HUMAN; IC 50; MALIGNANT NEOPLASTIC DISEASE; MYELODYSPLASTIC SYNDROME; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN TARGETING; REVIEW; T CELL LYMPHOMA;

CATALYTIC DOMAIN; DRUG DESIGN; ENZYME INHIBITORS; GENOME, HUMAN; HUMANS; MODELS, MOLECULAR; PHARMACOLOGY; PROTEIN METHYLTRANSFERASES;

EID: 69949148388     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd2974     Document Type: Review

References (80)

1. Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41-45 (2000).
2. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693-705 (2007).
3. Smith, B. C. & Denu, J. M. Chemical mechanisms of histone lysine and arginine modifications. Biochim. Biophys. Acta 1789, 45-57 (2008).
4. Cole, P. A. Chemical probes for histone-modifying enzymes. Nature Chem. Biol. 4, 590-597 (2008).
5. Keppler, B. R. & Archer, T. K. Chromatin-modifying enzymes as therapeutic targets - Part 1. Expert Opin. Ther. Targets. 12 1301-1312 (2008).
6. Pray, L. At the flick of a switch: Epigenetic drugs. Chem. Biol. 15, 640-641 (2008).
7. Jones, P. A. & Baylin, S. B. The epigenomics of cancer. Cell 128, 683-692 (2007).
8. Wilson, C. B., Rowell, E. & Sekimata, M. Epigenetic control of T-helper-cell differentiation. Nature Rev. Immunol. 9, 91-105 (2009).
9. Tsankova, N., Renthal, W., Kumar, A. & Nestler, E. J. Epigenetic regulation in psychiatric disorders. Nature Rev. Neurosci. 8 355-367 (2007).
10. Kleer, C. G. et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl Acad. Sci. USA 100, 11606-11611 (2003).
11. Krivtsov, A. V. et al. H3K79 methylation profiles define murine and human MLL-AF4 leukemias. Cancer Cell 14, 355-368 (2008).
12. Jansson, M. et al. Arginine methylation regulates the p53 response. Nature Cell Biol. 10, 1431-1439 (2008).
13. Hong, H. et al. Aberrant expression of CARM1, a transcriptional coactivator of androgen receptor, in the development of prostate carcinoma and androgen-independent status. Cancer 101, 83-89 (2004).
14. Schneider, R., Bannister, A. J. & Kouzarides, T. Unsafe SETs: Histone lysine methyltransferases and cancer. Trends Biochem. Sci. 27 396-402 (2002).
15. Simon, J. A. & Lange, C. A. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat. Res. 647, 21-29 (2008).
16. Dillon, S. C., Zhang, X., Trievel, R. C. & Cheng, X. The SET-domain protein superfamily: Protein lysine methyltransferases. Genome Biol. 6, 227 (2005).
17. Ryu, H. et al. ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease. Proc. Natl Acad. Sci. USA 103, 19176-19181 (2006).
18. Cheng, D., Cote, J., Shaaban, S. & Bedford, M. T. The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing. Mol. Cell 25, 71-83 (2007).
19. Li, Y. et al. Role of the histone H3 lysine 4 methyltransferase, SET7/9, in the regulation of NF-κB-dependent inflammatory genes. Relevance to diabetes and inflammation. J. Biol. Chem. 283, 26771-26781 (2008).
20. Covic, M. et al. Arginine methyltransferase CARM1 is a promoter-specific regulator of NF-κB-dependent gene expression. EMBO J. 24, 85-96 (2005).
21. Hassa, P. O., Covic, M., Bedford, M. T. & Hottiger, M. O. Protein arginine methyltransferase 1 coactivates NF-κB-dependent gene expression synergistically with CARM1 and PARP1. J. Mol. Biol. 377, 668-678 (2008).
22. Huang, J. et al. Trimethylation of histone H3 lysine 4 by Set1 in the lytic infection of human herpes simplex virus 1. J. Virol. 80, 5740-5746 (2006).
23. Jeong, S. J. et al. Coactivator-associated arginine methyltransferase 1 enhances transcriptional activity of the human T-cell lymphotropic virus type 1 long terminal repeat through direct interaction with Tax. J. Virol. 80, 10036-10044 (2006).
24. Cheng, X., Collins, R. E. & Zhang, X. Structural and sequence motifs of protein (histone) methylation enzymes. Annu. Rev. Biophys. Biomol. Struct. 34, 267-294 (2005).
25. Goldstein, D. M., Gray, N. S. & Zarrinkar, P. P. High-throughput kinase profiling as a platform for drug discovery. Nature Rev. Drug Discov. 7, 391-397 (2008).
26. Mook, R. A. The importance and complexity of target class selectivity in drug discovery. The American Association for Cancer Research Education Book 223-226 (The American Association for Cancer Research, Philadelphia, 2005).
27. Copeland, R. A. Evaluation of Enzyme Inhibitors in Drug Discovery: A Guide for Medicinal Chemists and Pharmacologists (Wiley, Hoboken, 2005).
28. Cheng, D. et al. Small molecule regulators of protein arginine methyltransferases. J. Biol. Chem. 279, 23892-23899 (2004).
29. Allis, C. D. et al. New nomenclature for chromatin-modifying enzymes. Cell 131, 633-636 (2007).
30. Zhang, X. & Bruice, T. C. Enzymatic mechanism and product specificity of SET-domain protein lysine methyltransferases. Proc. Natl Acad. Sci. USA 105, 5728-5732 (2008).
31. Federov, O. et al. A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc. Natl Acad. Sci. USA 104, 20523-20528 (2007).
32. Karaman, M. W. et al. A quantitative analysis of kinase inhibitor selectivity. Nature Biotech. 26, 127-132 (2008).
33. Min, J., Feng, Q., Li, Z., Zhang, Y. & Xu, R. M. Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase. Cell 112, 711-723 (2003).
34. Sawada, K. et al. Structure of the conserved core of the yeast Dot1p, a nucleosomal histone H3 lysine 79 methyltransferase. J. Biol. Chem. 279, 43296-43306 (2004).
35. Copeland, R. A. Enzymes: A Practical Introduction to Structure, Mechanism and Data Analysis 2nd edn (Wiley, Hoboken, 2000).
36. Couture, J. F., Hauk, G., Thompson, M. J., Blackburn, G. M. & Trievel, R. C. Catalytic roles for carbon-oxygen hydrogen bonding in SET domain lysine methyltransferases. J. Biochem. 281, 19280-19287 (2006).
37. Collins, R. E. et al. In vitro and in vivo analyses of a Phe/Tyr switch controlling product specificity of histone lysine methyltransferases. J. Biol. Chem. 280, 5563-5570 (2005).
38. Trievel, R. C., Flynn, E. M., Houtz, R. L. & Hurley, J. H. Mechanism of multiple lysine methylation by the SET domain enzyme ERubisco LSMT. Nature Struct. Biol. 10, 545-552 (2003).
39. Zhang, X. et al. Structural basis for the product specificity of histone lysine methyltransferases. Mol. Cell 12, 177-185 (2003).
40. Frederiks, F. et al. Nonprocessive methylation by Dot1 leads to functional redundancy of histone H3K79 methylation states. Nature Struct. Mol. Biol. 15, 550-557 (2008).
41. Chiang, P. K. Biological effects of inhibitors of S-adenosylhomocysteine hydrolase. Pharmacol. Ther. 77, 115-134 (1998).
42. Bender, C. M., Zingg, J.-M. & Jones, P. A. DNA methylation as a target for drug design. Pharm. Res. 15, 175-187 (1998).
43. Fiskus, W. et al. Panobinostat treatment depletes EZH2 and DNMT1 levels and enhances decitabine mediated de-repression of JunB and loss of survival of human acute leukemia cells. Cancer Biol. Ther. 8 939-950 (2009).
44. Chang, Y. et al. Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294. Nature Struct. Mol. Biol. 16, 312-317 (2009).
45. Allan, M. et al. N-Benzyl-1-heteroaryl-3-(trifluorometh yl -1H pyrazole-5-carboxamides as inhibitors of co-activator associated arginine methyltransferase 1 (CARM1). Bioorg Med. Chem. Lett. 19, 1218-1223 (2009).
46. Purandare, A. V. et al. Pyrazole inhibitors of coactivator associated arginine methyltransferase 1 (CARM1). Bioorg Med. Chem. Lett. 18, 4438-4441 (2008).
47. Huynh, T. et al. Optimization of pyrazole inhibitors of coactivator associated arginine methyltransferase 1 (CARM1). Bioorg Med. Chem. Lett. 19, 2924-2927 (2009).
48. Copeland, R. A., Gontarek, R. & Luo, L. in Textbook of Drug Design and Discovery 4th edn Ch. 12 (eds. Krogsgaard-Larsen, P., Madsen, U. & Stromgaard, K.) 378-407 (Taylor and Francis, New York, 2009).
49. Troffer-Charlier, N., Cura, V., Hassenboehler, P., Moras, D. & Cavarelli, J. Functional insights from structures of coactivator-associated arginine methyltransferase 1 domains. EMBO J. 26, 4391-4401 (2007).
50. Couture, J.-F., Collazo, E., Brunzelle, J. S. & Trievel, R. C. Structural and functional analysis of SET8, a histone H4 Lys-20 methyltransferase. Genes Dev. 19, 1455-1465 (2005).
51. Ma, W. W. & Adjei, A. A. Novel agents on the horizon for cancer therapy. CA Cancer J. Clin. 59, 111-137 (2009).
52. Cortez, C. C. & Jones, P. A. Chromatin, cancer and drug therapies. Mutat. Res. 647, 44-51 (2008).
53. Kang, M. Y. et al. Association of the SUV39H1 histone methyltransferase with the DNA methyltransferase 1 at mRNA expression level in primary colorectal cancer. Int. J. Cancer 121, 2192-2197 (2007).
54. Watanabe, H. et al. Deregulation of histone lysine methyltransferases contributes to oncogenic transformation of human bronchoepithelial cells. Cancer Cell Int. 8, 15 (2008).
55. Kondo, Y. et al. Downregulation of histone H3 lysine 9 methyltransferase G9a induces centrosome disruption and chromosome instability in cancer cells. PLoS One 3, e2037 (2008).
56. Tkachuk, D., Kohler, S. & Cleary, M. L. Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell 71, 691-700 (1992).
57. Gu, Y. et al. The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene. Cell 71, 701-708 (1992).
58. Liedtke, M. & Cleary, M. L. Therapeutic targeting of MLL. Blood 113, 6061-6068 (2009).
59. Wang, G. G., Cai, L., Pasillas, M. P. & Kamps, M. P. NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nature Cell Biol. 9, 804-812 (2007).
60. Marango, J. et al. The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor. Blood 111, 3145-3154 (2008).
61. Kim, J. Y. et al. Multiple-myeloma-related WHSC1/MMSET isoform RE-IIBP is a histone methyltransferase with transcriptional repression activity. Mol. Cell Biol. 28, 2023-2034 (2008).
62. Lauring, J. et al. The multiple myeloma associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity. Blood 111, 856-864 (2008).
63. Angrand, P. O. et al. NSD3, a new SET domain-containing gene, maps to 8p12 and is amplified in human breast cancer cell lines. Genomics 74, 79-88 (2001).
64. Rosati, R. et al. NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with t(8;11) (p11.2;p15). Blood 99 3857-3860 (2002).
65. Tonon, G. et al. High-resolution genomic profiles of human lung cancer. Proc. Natl Acad. Sci. USA 102, 9625-9630 (2005).
66. Okada, Y. et al. hDOT1L links histone methylation to leukemogenesis. Cell 121, 167-178 (2005).
67. Bitoun, E., Oliver, P. L. & Davies, K. E. The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling. Hum. Mol. Genet. 16, 92-106 (2007).
68. Hamamoto, R. et al. SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nature Cell Biol. 6, 731-740 (2004).
69. Hamamoto, R. et al. Enhanced SMYD3 expression is essential for the growth of breast cancer cells. Cancer Sci. 97, 113-118 (2006).
70. Bracken, A. P. et al. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J. 22 5323-5335 (2003).
71. Varambally, S. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624-629 (2002).
72. Subramanian, K. et al. Regulation of estrogen receptor alpha by the SET7 lysine methyltransferase. Mol. Cell 30, 336-347 (2008).
73. Nishikawa, N. et al. Gene amplification and overexpression of PRDM14 in breast cancers. Cancer Res. 67, 9649-9657 (2007).
74. Majumder, S., Liu, Y., Ford, O. H., 3rd, Mohler, J. L. & Whang, Y. E. Involvement of arginine methyltransferase CARM1 in androgen receptor function and prostate cancer cell viability. Prostate 66, 1292-1301 (2006).
75. Frietze, S., Lupien, M., Silver, P. A. & Brown, M. CARM1 regulates estrogen-stimulated breast cancer growth through up-regulation of E2F1. Cancer Res. 68, 301-306 (2008).
76. Zhao, Q. et al. PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing. Nature Struct. Mol. Biol. 16, 304-311 (2009).
77. Patnaik, D. et al. Substrate specificity and kinetic mechanism of mammalian G9a histone H3 methyltransferase. J. Biol. Chem. 279 53248-53258 (2004).
78. Chin, H. G., Patnaik, D., Esteve, P.-O., Jacobsen, S. E. & Pradhan, S. Catalytic properties and kinetic mechanism of human recombinant lys-9 histone H3 methyltransferase SUV39H1: Participation of the chromodomain in enzymatic catalysis. Biochemistry 45, 3272-3284 (2006).
79. Greiner, D., Bonaldi, T., Eskeland, R., Roemer, E. & Imhof, A. Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3-9. Nature Chem. Biol. 1, 143-145 (2005).
80. Kubicek, S. et al. Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol. Cell 25 473-481 (2007).