LLY-507, a cell-active, potent, and selective inhibitor of protein-lysine methyltransferase SMYD2

Journal of Biological Chemistry

Volumn 290, Issue 22, 2015, Pages 13641-13653

  Nguyen, Hannah ^a   Allali Hassani, Abdellah ^b   Antonysamy, Stephen ^a   Chang, Shawn ^a   Chen, Lisa Hong ^a   Curtis, Carmen ^a   Emtage, Spencer ^a   Fan, Li ^a   Gheyi, Tarun ^a   Li, Fengling ^b   Liu, Shichong ^d   Martin, Joseph R ^a   Mendel, David ^a   Olsen, Jonathan B ^a   Pelletier, Laura ^a   Shatseva, Tatiana ^b   Wu, Song ^a   Zhang, Feiyu Fred ^a   Arrowsmith, Cheryl H ^b,c   Brown, Peter J ^b   Campbell, Robert M ^a   Garcia, Benjamin A ^d   Barsyte Lovejoy, Dalia ^b   Mader, Mary ^a   Vedadi, Masoud ^b   more..

^a ELI LILLY AND COMPANY   (United States)

^b UNIVERSITY OF TORONTO   (Canada)

^c PRINCESS MARGARET HOSPITAL   (Canada)

^d UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALKYLATION; AMINO ACIDS; BINS; CELL CULTURE; CELLS; CRYSTAL STRUCTURE; CYTOLOGY; DATA MINING; DISEASES; DISSECTION; MASS SPECTROMETRY; MOBILE SECURITY; MOLECULAR BIOLOGY; MOLECULES; PROBES; SUBSTRATES;

BREAST CANCER CELLS; DOSE-DEPENDENT MANNER; HISTONE METHYLATION; SELECTIVE INHIBITORS; SMALL MOLECULE INHIBITOR; SUBCELLULAR FRACTIONATION; SUBMICROMOLAR CONCENTRATIONS; SUBSTRATE PEPTIDES;

PROTEINS;

HISTONE; LLY 507; METHYLTRANSFERASE; METHYLTRANSFERASE INHIBITOR; PROTEIN P53; PROTEIN SMYD2; UNCLASSIFIED DRUG; ANTINEOPLASTIC AGENT; BENZAMIDE DERIVATIVE; CHROMATIN; ENZYME INHIBITOR; HISTONE LYSINE METHYLTRANSFERASE; LLY-507; PEPTIDE; PYRROLIDINE DERIVATIVE; SMYD2 PROTEIN, HUMAN; TP53 PROTEIN, HUMAN;

ANTIPROLIFERATIVE ACTIVITY; ARTICLE; BREAST CANCER; CANCER CELL LINE; CELL FRACTIONATION; CHROMATIN; COMPUTER ANALYSIS; CONCENTRATION RESPONSE; CONTROLLED STUDY; CRYSTAL STRUCTURE; CYTOPLASM; DATA MINING; ENZYME ACTIVE SITE; ENZYME ACTIVITY; ENZYME ANALYSIS; ENZYME INHIBITOR COMPLEX; ENZYME SPECIFICITY; ESOPHAGUS CANCER; GENE AMPLIFICATION; HISTONE METHYLATION; HUMAN; IC50; LIVER CANCER; MASS SPECTROMETRY; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN METHYLATION; PROTEOMICS; ANTAGONISTS AND INHIBITORS; BIOLOGY; CELL PROLIFERATION; CHEMISTRY; CRYSTALLIZATION; DOSE RESPONSE; DRUG SCREENING; ENZYMOLOGY; GENETIC EPIGENESIS; METABOLISM; NEOPLASMS; PROTEIN DENATURATION; TUMOR CELL LINE; X RAY CRYSTALLOGRAPHY;

ANTINEOPLASTIC AGENTS; BENZAMIDES; CELL LINE, TUMOR; CELL PROLIFERATION; CHROMATIN; COMPUTATIONAL BIOLOGY; CRYSTALLIZATION; CRYSTALLOGRAPHY, X-RAY; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG SCREENING ASSAYS, ANTITUMOR; ENZYME INHIBITORS; EPIGENESIS, GENETIC; HISTONE-LYSINE N-METHYLTRANSFERASE; HISTONES; HUMANS; MASS SPECTROMETRY; NEOPLASMS; PEPTIDES; PROTEIN DENATURATION; PROTEOMICS; PYRROLIDINES; TUMOR SUPPRESSOR PROTEIN P53;

EID: 84930225536     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M114.626861     Document Type: Article

References (34)

1. Arrowsmith, C. H., Bountra, C., Fish, P. V., Lee, K., and Schapira, M. (2012) Epigenetic protein families: a new frontier for drug discovery. Nat. Rev. Drug Discov. 11, 384-400
2. Helin, K., and Dhanak, D. (2013) Chromatin proteins and modifications as drug targets. Nature 502, 480-488
3. Campbell, R. M., and Tummino, P. J. (2014) Cancer epigenetics drug discovery and development: the challenge of hitting the mark. J. Clin. Investig. 124, 64-69
4. Brown, M. A., Sims, R. J., 3rd, Gottlieb, P. D., and Tucker, P. W. (2006) Identification and characterization of Smyd2: a split SET/MYND domain-containing histone H3 lysine 36-specific methyltransferase that interacts with the Sin3 histone deacetylase complex. Mol. Cancer 5, 26-36
5. Gottlieb, P. D., Pierce, S. A., Sims, R. J., Yamagishi, H., Weihe, E. K., Harriss, J. V., Maika, S. D., Kuziel, W. A., King, H. L., Olson, E. N., Nakagawa, O., and Srivastava, D. (2002) Bop encodes a muscle-restricted protein containing MYND and SET domains and is essential for cardiac differentiation and morphogenesis. Nat. Genet. 31, 25-32
6. Tan, X., Rotllant, J., Li, H., De Deyne, P., and Du, S. J. (2006) SmyD1, a histone methyltransferase, is required for myofibril organization and muscle contraction in zebrafish embryos. Proc. Natl. Acad. Sci. U.S.A. 103, 2713-2718
7. Hamamoto, R., Furukawa, Y., Morita, M., Iimura, Y., Silva, F. P., Li, M., Yagyu, R., and Nakamura, Y. (2004) SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat. Cell Biol. 6, 731-740
8. Van Aller, G. S., Reynoird, N., Barbash, O., Huddleston, M., Liu, S., Zmoos, A. F., McDevitt, P., Sinnamon, R., Le, B., Mas, G., Annan, R., Sage, J., Garcia, B. A., Tummino, P. J., Gozani, O., and Kruger, R. G. (2012) Smyd3 regulates cancer cell phenotypes and catalyzes histone H4 lysine 5 methylation. Epigenetics 7, 340-343
9. Mazur, P. K., Reynoird, N., Khatri, P., Jansen, P. W., Wilkinson, A. W., Liu, S., Barbash, O., Van Aller, G. S., Huddleston, M., Dhanak, D., Tummino, P. J., Kruger, R. G., Garcia, B. A., Butte, A. J., Vermeulen, M., Sage, J., and Gozani, O. (2014) SMYD3 links lysine methylation of MAP3K2 to Rasdriven cancer. Nature 510, 283-287
10. Proserpio, V., Fittipaldi, R., Ryall, J. G., Sartorelli, V., and Caretti, G. (2013) The methyltransferase SMYD3 mediates the recruitment of transcriptional cofactors at the myostatin and c-Met genes and regulates skeletal muscle atrophy. Genes Dev. 27, 1299-1312
11. Hu, L., Zhu, Y. T., Qi, C., and Zhu, Y. J. (2009) Identification of Smyd4 as a potential tumor suppressor gene involved in breast cancer development. Cancer Res. 69, 4067-4072
12. Stender, J. D., Pascual, G., Liu, W., Kaikkonen, M. U., Do, K., Spann, N. J., Boutros, M., Perrimon, N., Rosenfeld, M. G., and Glass, C. K. (2012) Control of proinflammatory gene programs by regulated trimethylation and demethylation of histone H4K20. Mol. Cell 48, 28-38
13. Abu-Farha, M., Lambert, J. P., Al-Madhoun, A. S., Elisma, F., Skerjanc, I. S., and Figeys, D. (2008) The tale of two domains: proteomics and genomics analysis of SMYD2, a new histone methyltransferase. Mol. Cell. Proteomics 7, 560-572
14. Wu, J., Cheung, T., Grande, C., Ferguson, A. D., Zhu, X., Theriault, K., Code, E., Birr, C., Keen, N., and Chen, H. (2011) Biochemical characterization of human SET and MYND domain-containing protein 2 methyltransferase. Biochemistry 50, 6488-6497
15. Huang, J., Perez-Burgos, L., Placek, B. J., Sengupta, R., Richter, M., Dorsey, J. A., Kubicek, S., Opravil, S., Jenuwein, T., and Berger, S. L. (2006) Repression of p53 activity by Smyd2-mediated methylation. Nature 444, 629-632
16. Cho, H. S., Hayami, S., Toyokawa, G., Maejima, K., Yamane, Y., Suzuki, T., Dohmae, N., Kogure, M., Kang, D., Neal, D. E., Ponder, B. A., Yamaue, H., Nakamura, Y., and Hamamoto, R. (2012) RB1 methylation by SMYD2 enhances cell cycle progression through an increase of RB1 phosphorylation. Neoplasia 14, 476-486
17. Saddic, L. A., West, L. E., Aslanian, A., Yates, J. R., 3rd, Rubin, S. M., Gozani, O., Sage, J. (2010) Methylation of the retinoblastoma tumor suppressor by SMYD2. J. Biol. Chem. 285, 37733-37740
18. Abu-Farha, M., Lanouette, S., Elisma, F., Tremblay, V., Butson J., Figeys D, and Couture, J. F. (2011) Proteomic analyses of the SMYD family interactomes identify HSP90 as a novel target for SMYD2. J. Mol. Cell. Biol. 3, 301-308
19. Donlin, L. T., Andresen, C., Just, S., Rudensky, E., Pappas, C. T., Kruger, M., Jacobs, E. Y., Unger, A., Zieseniss, A., Dobenecker, M. W., Voelkel, T., Chait, B. T., Gregorio, C. C., Rottbauer, W., Tarakhovsky, A., and Linke, W. A. (2012) Smyd2 controls cytoplasmic lysine methylation of Hsp90 and myofilament organization. Genes Dev. 26, 114-119
20. Zhang, X., Tanaka, K., Yan, J., Li, J., Peng, D., Jiang, Y., Yang, Z., Barton, M. C., Wen, H., and Shi, X. (2013) Regulation of estrogen receptor α by histone methyltransferase SMYD2-mediated protein methylation. Proc. Natl. Acad. Sci. U.S.A. 110, 17284-17289
21. Jiang, Y., Trescott, L., Holcomb, J., Zhang, X., Brunzelle, J., Sirinupong, N., Shi, X., and Yang, Z. (2014) Structural insights into estrogen receptor α methylation by histone methyltransferase SMYD2, a cellular event implicated in estrogen signaling regulation. J. Mol. Biol. 426, 3413-3425
22. Piao, L., Kang, D., Suzuki, T., Masuda, A., Dohmae, N., Nakamura, Y., and Hamamoto, R. (2014) The histone methyltransferase SMYD2 methylates PARP1 and promotes poly(ADP-ribosyl)ation activity in cancer cells. Neoplasia 16, 257-264
23. Xu, S., Zhong, C., Zhang, T., and Ding, J. (2011) Structure of human lysine methyltransferase Smyd2 reveals insights into the substrate divergence in Smyd proteins. J. Mol. Cell. Biol. 3, 293-300
24. Wang, L., Li, L., Zhang, H., Luo, X., Dai, J., Zhou, S., Gu, J., Zhu, J., Atadja, P., Lu, C., Li, E., and Zhao, K. (2011) Structure of human SMYD2 protein reveals the basis of p53 tumor suppressor methylation. J. Biol. Chem. 286, 38725-38737
25. Ferguson, A. D., Larsen, N. A., Howard, T., Pollard, H., Green, I., Grande, C., Cheung, T., Garcia-Arenas, R., Cowen, S., Wu, J., Godin, R., Chen, H., and Keen, N. (2011) Structural basis of substrate methylation and inhibition of SMYD2. Structure 19, 1262-1273
26. Jiang, Y., Sirinupong, N., Brunzelle, J., Yang, Z. (2011) Crystal structures of histone and p53 methyltransferase SmyD2 reveal a conformational flexibility of the autoinhibitory C-terminal domain. PLoS One 6, e21640
27. Komatsu, S., Imoto, I., Tsuda, H., Kozaki, K. I., Muramatsu, T., Shimada, Y., Aiko, S., Yoshizumi, Y., Ichikawa, D., Otsuji, E., and Inazawa, J. (2009) Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous cell carcinoma. Carcinogenesis 30, 1139-1146
28. Skawran, B., Steinemann, D., Weigmann, A., Flemming, P., Becker, T., Flik, J., Kreipe, H., Schlegelberger, B., and Wilkens, L. (2008) Gene expression profiling in hepatocellular carcinoma: upregulation of genes in amplified chromosome regions. Mod. Pathol. 21, 505-516
29. Sakamoto, L. H., Andrade, R. V., Felipe, M. S., Motoyama, A. B., and Pittella Silva, F. (2014) SMYD2 is highly expressed in pediatric acute lymphoblastic leukemia and constitutes a bad prognostic factor. Leuk. Res. 38, 496-502
30. Niesen, F. H., Berglund, H., and Vedadi, M. (2007) The use of Differential Scanning Fluorimetry to detect ligand interactions that promote protein stability. Nat. Protoc. 2, 2212-2221
31. Collaborative Computational Project, Number 4 (1994) The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D Biol. Crystallogr. 50, 760-763
32. Diehl, F., Brown, M. A., van Amerongen, M. J., Novoyatleva, T., Wietelmann, A., Harriss, J., Ferrazzi, F., Böttger, T., Harvey, R. P., Tucker, P. W., and Engel, F. B. (2010) Cardiac deletion of Smyd2 is dispensable for mouse heart development. PLoS One 5, e9748
33. Barretina, J., Caponigro, G., Stransky, N., Venkatesan, K., Margolin, A. A., Kim, S., Wilson, C. J., Lehár, J., Kryukov, G. V., Sonkin, D., Reddy, A., Liu, M., Murray, L., Berger, M. F., Monahan, J. E., Morais, P., Meltzer, J., Korejwa, A., Jané-Valbuena, J., Mapa, F. A., Thibault, J., Bric-Furlong, E., Raman, P., Shipway, A., Engels, I. H., Cheng, J., Yu, G. K., Yu, J., Aspesi, P. Jr., de Silva, M., Jagtap, K., Jones, M. D., Wang, L., Hatton, C., Palescandolo, E., Gupta, S., Mahan, S., Sougnez, C., Onofrio, R. C., Liefeld, T., MacConaill, L., Winckler, W., Reich, M., Li, N., Mesirov, J. P., Gabriel, S. B., Getz, G., Ardlie, K., Chan, V., Myer, V. E., Weber, B. L., Porter, J., Warmuth, M., Finan, P., Harris, J. L., Meyerson, M., Golub, T. R., Morrissey, M. P., Sellers, W. R., Schlegel, R., and Garraway, L. A. (2012) The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603-607
34. Cerami, E., Gao, J., Dogrusoz, U., Gross, B. E., Sumer, S. O., Aksoy, B. A., Jacobsen, A., Byrne, C. J., Heuer, M. L., Larsson, E., Antipin, Y., Reva, B., Goldberg, A. P., Sander, C., and Schultz, N. (2012) The cBio Cancer Genomics Portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401-404