Cancer epigenetics drug discovery and development: The challenge of hitting the mark

Journal of Clinical Investigation

Volumn 124, Issue 1, 2014, Pages 64-69

  Campbell, Robert M ^a   Tummino, Peter J ^b  

^a ELI LILLY AND COMPANY   (United States)

^b GLAXOSMITHKLINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; BET INHIBITOR; DOT1L INHIBITOR; EZH2 INHIBITOR; TRANSCRIPTION FACTOR EZH2; UNCLASSIFIED DRUG;

CANCER GENETICS; DRUG TARGETING; EPIGENETICS; GENE CONTROL; HUMAN; NONHUMAN; PRIORITY JOURNAL; PROTEIN TARGETING; REVIEW;

EID: 84892919442     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI71605     Document Type: Review

References (71)

1. Varier RA, Timmers HT. Histone lysine methylation and demethylation pathways in cancer. Biochim Biophys Acta. 2011;1815(1):75-89
2. Baylin SB, Jones PA. A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer. 2011;11(10):726-734
3. Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet. 2009; 10(10):704-714
4. Smiraglia DJ, et al. Excessive CpG island hypermethylation in cancer cell lines versus primary human malignancies. Hum Mol Genet. 2001; 10(13):1413-1419
5. Paz MF, et al. A systematic profile of DNA methylation in human cancer cell lines. Cancer Res. 2003; 63(5):1114-1121
6. Sneeringer CJ, et al. Coordinated activities of wildtype plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc Natl Acad Sci U S A. 2010;107(49):20980-20985
7. Yap DB, et al. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood. 2011;117(8):2451-2459
8. McCabe MT, et al. Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc Natl Acad Sci U S A. 2012; 109(8):2989-2994
9. Keats JJ, Reiman T, Belch AR, Pilarski LM. Ten years and counting: so what do we know about t(4;14) (p16;q32) multiple myeloma. Leuk Lymphoma. 2006; 47(11):2289-2300
10. Lauring J, et al. The multiple myeloma associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity. Blood. 2008; 111(2):856-864
11. Martinez-Garcia E, et al. The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. Blood. 2011;117(1):211-220
12. Kuo AJ, et al. NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming. Mol Cell. 2011;44(4):609-620
13. Shen H, Laird PW. Interplay between the cancer genome and epigenome. Cell. 2013;153(1):38-55
14. Wilson BG, Roberts CW. SWI/SNF nucleosome remodellers and cancer. Nat Rev Cancer. 2011; 11(7):481-492
15. Romero OA, Sanchez-Cespedes M. The SWI/SNF genetic blockade: effects in cell differentiation, cancer and developmental diseases [published online ahead of print June 10, 2013]. Oncogene. doi:10.1038/onc.2013.227
16. Versteege I, et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature. 1998; 394(6689):203-206
17. Jackson EM, et al. Genomic analysis using highdensity single nucleotide polymorphism-based oligonucleotide arrays and multiplex ligation-dependent probe amplification provides a comprehensive analysis of INI1/SMARCB1 in malignant rhabdoid tumors. Clin Cancer Res. 2009;15(6):1923-1930
18. Wilson BG, et al. Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell. 2010;18(4):316-328
19. Knutson SK, et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci U S A. 2013;110(19):7922-7927
20. Vedadi M, et al. A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Nat Chem Biol. 2011;7(8):566-574
21. Konze KD, et al. An orally bioavailable chemical probe of the lysine methyltransferases EZH2 and EZH1. ACS Chem Biol. 2013;8(6):1324-1334
22. Yu W, et al. Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nat Commun. 2012;3:1288
23. James LI, et al. Discovery of a chemical probe for the L3MBTL3 methyllysine reader domain. Nat Chem Biol. 2013;9(3):184-191
24. Filippakopoulos P, et al. Selective inhibition of BET bromodomains. Nature. 2010;468(7327):1067-1073
25. Fish PV, et al. Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit. J Med Chem. 2012;55(22):9831-9837
26. Liu F, et al. Exploiting an allosteric binding site of PRMT3 yields potent and selective inhibitors. J Med Chem. 2013;56(5):2110-2124
27. Wu J, et al. Biochemical characterization of human SET and MYND domain-containing protein 2 methyltransferase. Biochemistry. 2011;50(29):6488-6497
28. Li Y, et al. The target of the NSD family of histone lysine methyltransferases depends on the nature of the substrate. J Biol Chem. 2009; 284(49):34283-34295
29. McCabe MT, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012;492(7427):108-112
30. Knutson SK, et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol. 2012;8(11):890-896
31. Jung HR, Pasini D, Helin K, Jensen ON. Quantitative mass spectrometry of histones H3.2 and H3.3 in Suz12-deficient mouse embryonic stem cells reveals distinct, dynamic post-translational modifications at Lys-27 and Lys-36. Mol Cell Proteomics. 2010;9(5):838-850
32. Diaz E, et al. Development and validation of reagents and assays for EZH2 peptide and nucleosome high-throughput screens. J. Biomol. Screen. 2012;17(10):1279-1292
33. Qi W, et al. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc Natl Acad Sci U S A. 2012;109(52):21360- 21365
34. Verma SK, et al. Identification of potent, selective, cell-active inhibitors of the histone lysine methyltransferase EZH2. ACS Med Chem Lett. 2012; 3(12):1091-1096
35. Albrecht BK, Audia JE, Gagnon A, Harmange JC, Naveschuk CG, inventors. Constellation Pharmaceuticals, assignee. Modulators of methyl modifying enzymes, compositions uses thereof. US patent application PCT/US2012/065796. November 19, 2012
36. Margueron R, et al. Role of the polycomb protein EED in the propagation of repressive histone marks. Nature. 2009;461(7265):762-767
37. Van Aller GS, et al. Long residence time inhibition of EZH2 in activated polycomb repressive complex 2 [published online ahead of print December 4, 2013]. ACS Chem Biol. doi:10.1021/cb4008748
38. Feng Q, et al. Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain. Curr Biol. 2002;12(12):1052-1058
39. Aplan PD. Chromosomal translocations involving the MLL gene: molecular mechanisms. DNA Repair (Amst). 2006;5(9-10):1265-1272
40. Bitoun E, Oliver PL, Davies KE. The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling. Hum Mol Genet. 2007;16(1):92-106
41. Mueller D, et al. A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification. Blood. 2007;110(13):4445-4454
42. Mueller D, Garcia-Cuellar MP, Bach C, Buhl S, Maethner E, Slany RK. Misguided transcriptional elongation causes mixed lineage leukemia. PLoS Biol. 2009;7(11):e1000249
43. Daigle SR, et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell. 2011;20(1):53-65
44. Bernt KM, et al. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell. 2011;20(1):66-78
45. Chen L, et al. Abrogation of MLL-AF10 and CALMAF10- mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l. Leukemia. 2013; 27(4):813-822
46. Yao Y, et al. Selective inhibitors of histone methyltransferase DOT1L: design, synthesis, and crystallographic studies. J Am Chem Soc. 2011; 133(42):16746-16749
47. Basavapathruni A, et al. Conformational adaptation drives potent, selective and durable inhibition of the human protein methyltransferase DOT1L. Chem Biol Drug Des. 2012;80(6):971-980
48. Yu W, et al. Bromo-deaza-SAH: a potent and selective DOT1L inhibitor. Bioorg Med Chem. 2013; 21(7):1787-1794
49. Arrowsmith CH, Bountra C, Fish PV, Lee K, Schapira M. Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov. 2012; 11(5):384-400
50. Jang MK, Mochizuki K, Zhou M, Jeong HS, Brady JN, Ozato K. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol Cell. 2005;19(4):523-534
51. Yang Z, et al. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol Cell. 2005;19(4):535-545
52. French CA. Demystified molecular pathology of NUT midline carcinomas. J Clin Pathol. 2010; 63(6):492-496
53. French CA, et al. BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene. 2008;27(15):2237-2242
54. Chung C-W, et al. Discovery and characterization of small molecule inhibitors of the BET family bromodomains. J Med Chem. 2011;54(11):3827-3838
55. Miyoshi S, Ooike S, Iwata K, Hikawa K, Sugahara K, inventors. Mitsubishi Tanabe Pharma Corporation, assignee. Antitumor agent. International patent PCT/JP2008/073864. September 7, 2009
56. Adachi K, et al. Thienotriazolodiazepine compound medicinal use thereof. International patent PCT/JP2006/310709. July 12, 2006
57. Nicodeme E, et al. Suppression of inflammation by a synthetic histone mimic. Nature. 2010; 468(7327):1119-1123
58. Dawson MA, et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature. 2011;478(7370):529-533
59. Picaud S, et al. PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains. Cancer Res. 2013;73(11):3336-3346
60. Delmore JE, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011; 146(6):904-917
61. Mertz JA, et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A. 2011;108(40):16669-16674
62. Puissant A, et al. Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013;3(3):308-323
63. Wyce A, et al. BET inhibition silences expression of MYCN and BCL2 and induces cytotoxicity in neuroblastoma tumor models. PLoS One. 2013; 8(8):e72967
64. Dawson MA, Kouzarides T, Huntly BJ. Targeting epigenetic readers in cancer. N Engl J Med. 2012; 367(7):647-657
65. Nikoloski G, et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet. 2010;42(8):665-667
66. Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP. CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A. 1999; 96(15):8681-8686
67. Weisenberger DJ, et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006; 38(7):787-793
68. Matei D, et al. Epigenetic resensitization to platinum in ovarian cancer. Cancer Res. 2012;72(9):2197-2205
69. Juergens RA, et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 2011; 1(7):598-607
70. Slany RK. The molecular biology of mixed lineage leukemia. Haematologica. 2009;94(7):984-993
71. Chiang CM. Brd4 engagement from chromatin targeting to transcriptional regulation: selective contact with acetylated histone H3 and H4. F1000 Biol Rep. 2009;1:98.