Histone deacetylase inhibitors: Recent insights from basic to clinical knowledge & patenting of anti-cancer actions

Recent Patents on Anti-Cancer Drug Discovery

Volumn 6, Issue 1, 2011, Pages 131-145

  Carafa, Vincenzo ^a   Nebbioso, Angela ^a   Altucci, Lucia ^a,b  

^a SECOND UNIVERSITY OF NAPLES   (Italy)

^b CNRIGB   (Italy)

Author keywords

Cancer; Epigenetics; Hdac inhibitors; Human diseases; Neurodegeneration; Signal transduction

Indexed keywords

4 PHENYLBUTYRIC ACID; BELINOSTAT; BEXAROTENE; DACINOSTAT; EL 532; ENTINOSTAT; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; EPIRUBICIN; ERLOTINIB; ESTROGEN RECEPTOR ALPHA; GIVINOSTAT; HISTONE DEACETYLASE INHIBITOR; HYDROXAMIC ACID DERIVATIVE; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MOCETINOSTAT; PANOBINOSTAT; PCI 24781; PDX 101; PEMETREXED; PIVALOYLOXYMETHYL BUTYRATE; PROTEASOME INHIBITOR; PYROXAMIDE; ROMIDEPSIN; ROSCOVITINE; TACEDINALINE; UNCLASSIFIED DRUG; VALPROIC ACID; VORINOSTAT; VP 101; YM 753;

ACUTE GRANULOCYTIC LEUKEMIA; ACUTE LYMPHOCYTIC LEUKEMIA; ACUTE MYELOBLASTIC LEUKEMIA; ADVANCED CANCER; ANEMIA; ANOREXIA; ANTIANGIOGENIC ACTIVITY; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER COMBINATION CHEMOTHERAPY; CANCER RESISTANCE; CARDIOTOXICITY; CELLULAR DISTRIBUTION; CHEMOTHERAPY INDUCED EMESIS; CHROMATIN ASSEMBLY AND DISASSEMBLY; CUTANEOUS T CELL LYMPHOMA; DRUG APPROVAL; DRUG EFFICACY; DRUG INDICATION; DRUG MEGADOSE; ELECTROLYTE BLOOD LEVEL; FATIGUE; GASTROINTESTINAL TOXICITY; GENE ACTIVATION; GENE EXPRESSION REGULATION; GENE LOCATION; GENE MUTATION; HEART CONDUCTION; HEART LEFT VENTRICLE FUNCTION; HEMATOLOGIC MALIGNANCY; HISTONE ACETYLATION; HODGKIN DISEASE; HUMAN; INFECTION; INFLAMMATION; LEUKEMIA RELAPSE; LEUKOPENIA; LYMPHOMA; MALIGNANT NEOPLASTIC DISEASE; MOLECULAR DYNAMICS; MULTIPLE MYELOMA; MYELODYSPLASTIC SYNDROME; NAUSEA; NONHODGKIN LYMPHOMA; NONHUMAN; PATENT; PRIORITY JOURNAL; RECOMMENDED DRUG DOSE; SIDE EFFECT; SKIN MANIFESTATION; SOLID TUMOR; STRUCTURE ACTIVITY RELATION; TASTE DISORDER; THROMBOCYTOPENIA; TRANSCRIPTION REGULATION; TUMOR MICROENVIRONMENT; UNSPECIFIED SIDE EFFECT;

ALGORITHMS; ANTINEOPLASTIC AGENTS; BIOMEDICAL RESEARCH; HISTONE DEACETYLASE INHIBITORS; HUMANS; KNOWLEDGE; MEDICAL ONCOLOGY; MODELS, BIOLOGICAL; PATENTS AS TOPIC;

EID: 78650955928     PISSN: 15748928     EISSN: None     Source Type: Journal    
DOI: 10.2174/157489211793980088     Document Type: Article

References (224)

1. Hahn WC, Weinberg RA. Rules for making human tumor cells. N Engl J Med 2002; 347: 1593-603
2. Bernstein BE, Meissner A, Lander ES. The mammalian epigenome. Cell 2007; 23: 669-81
3. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev 2002; 16: 6-21
4. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002; 3: 415-28
5. Feinberg AP, Tycko B. The history of cancer epigenetics. Nat Rev Cancer 2004; 4: 143-53
6. Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of human cancer. Nat Rev Gene 2006; 7: 21-33
7. Strahl BD, Allis CD. The language of covalent histone modifications. Nature 2000; 403: 41-45
8. Jenuwein T, Allis CD. Translating the histone code. Science 2001; 293: 1074-80
9. Shukla V, Vaissiere T, Herceg Z. Histone acetylation and chromatin signature in stem cell identity and cancer. Mutat Res 2007; 637(1-2): 1-15
10. Nightingale KP, O'Neill LP, Turner BM. Histone modifications: Signalling receptors and potential elements of a heritable epigenetic code. Curr Opin Genet Dev 2006; 16: 125-36
11. Kurdistani SK, Grunstein M. Histone acetylation and deacetylation in yeast. Nat Rev Mol Cell Biol 2003; 4: 276-84
12. Hake SB, Xiao A, Allis CD. Linking the epigenetic 'language' of covalent histone modifications to cancer. Br J Cancer 2004; 90: 761-9
13. Robertson KD, Jones PA. DNA methylation: Past, present and future directions. Carcinogenesis 2000; 21: 461-7
14. Kadosh D, Struhl K. Repression by Ume6 involves recruitment of a complex containing Sin3 corepressor and Rpd3 histone deacetylase to target promoters. Cell 1997; 89: 365-71
15. Kuo MH, Allis CD. Roles of histone acetyltransferases and deacetylases in gene regulation. Bioessays 1998; 20: 615-26
16. Ruijter DMJ, Annmieke GVHA, Huib CN, Kemp S, Kuilenburg VPBA. Histone deacetylases (HDACs): Characterization of the classical HDAC family. Biochem J 2003; 370: 737-49
17. Gregoretti IV, Lee YM, Goodson HV. Molecular evolution of the histone deacetylase family: Functional implications of phylogenetic analysis. J Mol Biol 2004; 338:17-31
18. Taunton J, Hassig CA, Schreiber SL. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 1996; 272: 408-11
19. Rundlett SE, Carmen AA, Kobayashi R, Bavykin S, Turner BM, Grunstein M. HDA1 and RPD3 are members of distinct yeast histone deacetylase complexes that regulate silencing and transcription. Proc Natl Acad Sci USA 1996; 93: 14503-8
20. Wang AH, Bertos NR, Vezmar M, Pelletier N, Crosato M, Heng HH, et al. HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional corepressor. Mol Cell Biol 1999; 19: 7816-27
21. Grozinger CM, Schreiber SL. Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3- dependent cellular localization. Proc Natl Acad Sci USA 2000; 97: 7835-40
22. Verdel A, Curtet S, Brocard MP, Rousseaux S, Lemercier C, Yoshida M, et al. Active maintenance of Mhda2/Mhdac6 histonedeacetylase in the cytoplasm. Curr Biol 2000; 10: 747-9
23. Kao HY, Downes M, Ordentlich P, Evans RM. Isolation of a novel histone deacetylase reveals that class I and class ii deacetylases promote smrt-mediated repression. Genes Dev 2000; 14: 55-66
24. Dressel U, Bailey PJ, Wang SC, Downes M, Evans RM, Muscat GE. A dynamic role for HDAC7 in MEF2-mediated muscle differentiation. J Biol Chem 2001; 276: 17007-13
25. Gray SG, Ekstrom TJ. The human histone deacetylase family. Exp Cell Res 2001; 262: 75-83
26. Kao HY, Lee CH, Komarov A, Han CC, Evans RM. Isolation and characterization of mammalian HDAC10, a novel histone deacetylase. J Biol Chem 2002; 277: 187-93
27. Gao L, Cueto MA, Asselbergs F, Atadja P. Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family. J Biol Chem 2002; 277: 25748-55
28. Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD dependent histone deacetylase. Nature 2000; 403: 795-800
29. Finnin MS, Donigian JR, Pavletich NP. Structure of the histone deacetylase SIRT2. Nat Struct Biol 2001; 8: 621-5
30. Glozak MA, Seto E. Histone deacetylases and cancer. Oncogene 2007; 26: 5420-32
31. Juan LJ, Shia WJ, Chen MH, Yang WM, Seto E, Lin YS, et al. Histone deacetylases specifically down-regulate P53-dependent gene activation. J Biol Chem 2000; 275: 20436-43
32. Imhof A, Yang XJ, Ogryzko VV, Nakatani Y, Wolffe AP, Ge H. Acetylation of general transcription factors by histone acetyltransferases. Curr Biol 1997; 7: 689-92
33. Boyes J, Byfield P, Nakatani Y, Ogryzko V. Regulation of activity of the transcription factor GATA-1 by acetylation. Nature 1998; 396: 594-8
34. Vigushin DM, Ali S, Pace PE, Mirsaidi N, Ito K, Adcock I, et al. Trichostatin A is A histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo. Clin Cancer Res 2001; 7: 971-6
35. Wang C, Fu M, Angeletti RH, Siconolfi-Baez L, Reutens AT, Albanese C, et al. Direct acetylation of the estrogen receptor alpha hinge region by P300 Regulates transactivation and hormone sensitivity. J Biol Chem 2001; 276: 18375-83
36. Cress WD, Seto E. Histone deacetylases, transcriptional control, and cancer. J Cell Physiol 2000; 184: 1-16
37. Timmermann S, Lehrmann H, Polesskaya A, Harel-Bellan A. Histone acetylation and disease. Cell Mol Life Sci 2001; 58: 728-36
38. Munster PN, Sandoval TT, Rosen N, Rifkind R, Marks PA, Richon VM. The histone deacetylase inhibitor suberoyanilide hydroxamic acid induces differentiation of human breast cancer cells. Cancer Res 2001; 61: 8492-7
39. Tsuji N, Kobayashi M, Nagashima K, Wakisaka Y, Koizumi K. A new antifungal antibiotic Trichostatin. J Antibiot 1976; 29: 1-6
40. Yoshida M, Kijima M, Akita M, Beppu T. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by Trichostatin A. J Biol Chem 1990; 265: 17174-9
41. Kim YB, Lee KH, Sugita K, Yoshida M, Horinouchi S. Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase. Oncogene 1999; 18: 2461-70
42. Richon VM, Emiliani S, Verdin E, Webb Y, Breslow R, Rifkind RA, et al. A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc Natl Acad Sci USA 1998; 95: 3003-7
43. Butler LM, Webb Y, Agus DB, Higgins B, Tolentino TR, Kutko MC, et al. Inhibition of transformed cell growth and induction of cellular differentiation by pyroxamide. An inhibitor of histone deacetylase. Clin Cancer Res 2001; 7: 962-70
44. Kijima M, Yoshida M, Sugita K, Horinouchi S, Beppu T. Trapoxin, an antitumor cyclic tetrapeptide. Is an irreversible inhibitor of mammalian histone deacetylase. J Biol Chem 1993; 268: 22429-35
45. Hirota A, Suzuki A, Aizawa K, Tamura S. Mass spectrometric determination of amino acid sequence in Cyl-2, a novel cyclotetrapeptide from cylindrocladium scoparium. Biomed Mass Spectrom 1974; 1: 15-9
46. Kawai M, Rich DH, Walton JD. The structure and conformation of HC-toxin. Biochem Biophys Res Commun 1983; 111: 398-403
47. Umehara K, Nakahara K, Kiyoto S, Iwami M, Okamoto M, Tanaka H, et al. Studies on WF- 3161, a new antitumor antibiotic. J Antibiot (Tokyo) 1983; 36: 478-83
48. Closse A, Huguenin R. Isolation and structural clarification of chlamydocin. Helv Chim Acta 1974; 57: 533-45
49. Darkin-Rattray SJ, Gurnett AM, Myers RW, Dulski PM, Crumley TM, Allocco JJ, et al. Apicidin: A novel antiprotozoal agent that inhibits parasite histone deacetylase. Proc Natl Acad Sci USA 1996; 93: 13143-7
50. Nakajima H, Kim YB, Terano H, Yoshida M, Horinouchi S. FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. Exp Cell Res 1998; 241: 126-33
51. Newmark HL, Lupton JR, Young CW. Butyrate as a differentiating agent: Pharmacokinetics, analogues and current status. Cancer Lett 1994; 78: 1-5
52. Warrell RP Jr, He LZ, Richon V, Calleja E, Pandolfi PP. therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Natl Cancer Inst 1998; 90: 1621-5
53. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 2001; 25: 25-30
54. Saito A, Yamashita T, Mariko Y, Nosaka Y, Tsuchiya K, Ando T, et al. A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. Proc Natl Acad Sci USA 1999; 96: 4592-7
55. Kwon HJ, Owa T, Hassig CA, Shimada J, Schreiber SL. Depudecin induces morphological reversion of transformed fibroblasts via the inhibition of histone deacetylase. Proc Natl Acad Sci USA 1998; 95: 3356-61
56. Breslow R, Jursic B, Yan ZF, Friedman E, Leng L, Ngo L, et al. Potent cytodifferentiating agents related to hexamethylenebisacetamide. Proc Natl Acad Sci USA 1991; 88: 5542-6
57. Finnin MS, Donigian JR, Cohen A, Richon VM, Rifkind RA, Marks PA, et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 1999; 401: 188-93
58. Bernstein BE, Tong JK, Schreiber SL. Genomewide studies of histone deacetylase function in yeast. Proc Natl Acad Sci USA 2000; 97: 13708-13
59. Haggarty SJ, Koeller KM, Wong JC, Grozinger CM, Schreiber SL. Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc Natl Acad Sci USA 2003; 100: 4389-9
60. Somoza JR, Skene RJ, Katz BA, Mol C, Ho JD, Jennings AJ, et al. Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure 2004; 12: 1325-34
61. Kozikowski AP, Chen Y, Gaysin A, Chen B, D'Annibale MA, Suto CM, et al. Functional differences in epigenetic modulatorssuperiority of mercaptoacetamide-based histone deacetylase inhibitors relative to hydroxamates in cortical neuron neuroprotection studies. J Med Chem 2007; 50: 3054-61
62. Rasheed WK, Johnstone RW, Prince HM. Histone deacetylase inhibitors in cancer therapy. Expert Opin Invest Drugs 2007; 16: 659-78
63. Butler KV, Kozikowski AP. Chemical origins of isoform selectivity in histone deacetylase inhibitors. Curr Pharm Des 2008; 14: 505-28
64. Estiu G, Greenberg E, Harrison CB, Kwiatkowski NP, Mazitschek R, Bradner JE, et al. Structural origin of selectivity in class IIselective histone deacetylase inhibitors. J Med Chem 2008; 51: 2898-906
65. Khan N, Jeffers M, Kumar S, Hackett C, Boldog F, Khramtsov N, et al. Determination of the class and isoform selectivity of smallmolecule histone deacetylase inhibitors. Biochem J 2008; 409: 581-9
66. Moradei O, Vaisburg A, Martell RE. Histone deacetylase inhibitors in cancer therapy: New compounds and clinical update of benzamide-type agents. Curr Top Med Chem 2008; 8: 841-58
67. Jones P, Bottomley MJ, Carfi A, Cecchetti O, Ferrigno F, Lo Surdo P, et al. 2- Trifluoroacetylthiophenes, a novel series of potent and selective class II histone deacetylase inhibitors. Bioorg Med Chem Lett 2008; 18: 3456-61
68. Bolden JE, Peart MJ, Johnstone RW. Anti-cancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 2006; 5: 769-84
69. Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 2006; 6: 38-51
70. Jones PA, Baylin SB. The epigenomics of cancer. Cell 2007; 128: 683-92
71. Xu WS, Parmigiani RB, Marks PA. Histone deacetylase inhibitors: Molecular mechanisms of action. Oncogene 2007; 26: 5541-52
72. Dokmanovic M, Clarke C, Marks PA. Histone deacetylase inhibitors: Overview and perspectives. Mol Cancer Res 2007; 5: 981-9
73. Blackwell L, Norris J, Suto CM, Janzen WP. The use of diversity profiling to characterize chemical modulators of the histone deacetylases. Life Sci 2008; 82: 1050-8
74. Shankar S, Srivastava RK. Histone deacetylase inhibitors: Mechanisms and clinical significance in cancer: HDAC inhibitorinduced apoptosis. Adv Exp Med Biol 2008; 615: 261-98
75. Burgess A, Ruefli A, Beamish H, Warrener R, Saunders N, Johnstone R, et al. Histone deacetylase inhibitors specifically kill nonproliferating tumour cells. Oncogene 2004; 23: 6693-701
76. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. Core signalling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321: 1801-6
77. Peart MJ, Smyth GK, van Laar RK, Bowtell DD, Richon VM, Marks PA, et al. Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc Natl Acad Sci USA 2005; 102: 3697-702
78. Gui CY, Ngo L, Xu WS, Richon VM, Marks PA. Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoterassociated proteins, including HDAC1. Proc Natl Acad Sci USA 2004; 101: 1241-6
79. Rosato RR, Maggio SC, Almenara JA, Payne SG, Atadja P, Spiegel S, et al. The histone deacetylase inhibitor LAQ824 induces human leukemia cell death through a process involving XIAP down-regulation, oxidative injury, and the acid sphingomyelinasedependent generation of ceramide. Mol Pharmacol 2006; 69: 216-25
80. Robbins AR, Jablonski SA, Yen TJ, Yoda K, Robey R, Bates SE, et al. Inhibitors of histone feacetylases alter kinetochore assembly by disrupting pericentromeric heterochromatin. Cell Cycle 2005; 4: 717-26
81. Xu WS, Parmigiani RB, Marks PA. Histone deacetylase inhibitors: Molecular mechanisms of action. Oncogene 2007; 26: 5541-52
82. Oh M, Choi IK, Kwon HJ. Inhibition of histone deacetylase1 induces autophagy. Biochem Biophys Res Commun 2008; 369: 1179-83
83. Yamamoto S, Tanaka K, Sakimura R, Okada T, Nakamura T, Li Y, et al. Suberoylanilide hydroxamic acid (SAHA) induces apoptosis or autophagy-associated cell death in chondrosarcoma cell lines. Anti-Cancer Res 2008; 28: 1585-91
84. Hideshima T, Bradner JE, Wong J, Chauhan D, Richardson P, Schreiber SL, et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci USA 2005; 102: 8567-72
85. Fantin VR, Richon VM. Mechanisms of resistance to histone deacetylase inhibitors and their therapeutic implications. Clin Cancer Res 2007; 13: 7237-42
86. Rosato RR, Almenara JA, Maggio SC, Coe S, Atadja P, Dent P, et al. Role of histone deacetylase inhibitor-induced ROS and DNA damage in LAQ-824/fludarabine antileukemic interactions. Mol Cancer Ther 2008; 7: 3285-97
87. Rosato RR, Kolla SS, Hock SK, Almenara JA, Patel A, Amin S, et al. HDAC inhibitors activate NF-kB in human leucemia cells through an ATM/nemo -related pathway. JBC 2010; 285(13): 10064-77
88. Nonn L, Berggren M, Powis G. Increased expression of mitochondrial peroxiredoxin-3 (thioredoxin peroxidase-2) protects cancer cells against hypoxia and drug-induced hydrogen peroxidedependent apoptosis. Mol Cancer Res 2003; 1: 682-9
89. Parmigiani RB, Xu WS, Venta-Perez G, Erdjument-Bromage H, Yaneva M, Tempst P, et al. HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation. Proc Natl Acad Sci USA 2008; 105: 9633-8
90. Nolan L, Johnson PW, Ganesan A, Packham G, Crabb SJ. Will histone deacetylase inhibitors require combination with other agents to fulfil their therapeutic potential? Br J Cancer 2008; 99: 689-94
91. Carew JS, Giles FJ, Nawrocki ST. Histone deacetylase inhibitors: Mechanisms of cell death and promise in combination cancer therapy. Cancer Lett 2008; 269: 7-17
92. Tambaro FP, Dell'Aversana C, Carafa V, Nebbioso A, Radic B, Ferrara F, et al. Histone deacetylase inhibitors: Clinical implications for hematological malignancies. Clin Epigenet (in press) DOI 10.1007/s13148-010-0006-2
93. Cang S, Ma Y, Liu D. New clinical developments in histone deacetylase inhibitors for epigenetic therapy of cancer. J Hematol Oncol 2009; 2: 22
94. Marks PA, Breslow R. Dimethyl sulfoxide to vorinostat: Development of this histone deacetylase inhibitor as an anti-cancer drug. Nat Biotechnol 2007; 25: 84-90
95. Duvic M, Vu J. Vorinostat: A new oral histone deacetylase inhibitor approved for cutaneous T-cell lymphoma. Expert Opin Invest Drugs 2007; 16: 1111-20
96. Khan N, Jeffers M, Kumar S, Hackett C, Boldog F, Khramtsov N, et al. Determination of the class and isoform selectivity of small molecule histone deacetylase inhibitors. Biochem J 2008; 15: 581-9
97. Somoza JR, Skene RJ, Katz BA, Mol C, Ho JD, Jennings AJ, et al. Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure 2004; 12(7): 1325-34
98. Vannini A, Volpari C, Filocamo G, Casavola EC, Brunetti M, Renzoni D, et al. Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proc Natl Acad Sci USA 2004; 101(42): 15064-9
99. O'Connor OA, Heaney ML, Schwartz L, Richardson S, Willim R, MacGregor-Cortelli B, et al. Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. J Clin Oncol 2006; 24: 166-73
100. Crump M, Coiffier B, Jacobsen ED, Sun L, Ricker JL, Xie H, et al. Phase II trial of oral Vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large- B-cell lymphoma. Ann Oncol 2008; 19: 964-9
101. Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R. FDA approval summary: Vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 2007; 12: 1247-52
102. Fantin VR, Loboda A, Paweletz CP, Hendrickson RC, Pierce JW, Roth JA, et al. Constitutive activation of signal transducers and activators of transcription predicts Vorinostat resistance in cutaneous T-cell lymphoma. Cancer Res 2008; 68: 3785-94
103. Kirschbaum MH, Goldman BH, Zain JM, Cook JR, Rimsza LM, Forman SJ, et al. Vorinostat (suberoylanilide hydroxamic acid) in relapsed or refractory Hodgkin lymphoma: SWOG 0517. Blood (ASH annual meeting abstracts) 2007; 110: 2574
104. Kirschbaum MH, Zain JM, Popplewell L, Pullarkat V, Nademanee AP, Delioukina ML, et al. A phase 2 study of Vorinostat (suberoylanilide hydroxamic acid, SAHA) in relapsed or refractory indolent non Hodgkin lymphoma. A California Cancer Consortium Study. Blood (ASH annual meeting abstracts) 2007; 110: 2568
105. Garcia-Manero G, Yang H, Bueso-Ramos C, Ferrajoli A, Cortes J, Wierda WG, et al. Phase 1 study of the histone deacetylase inhibitor Vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood 2008; 111: 1060-6
106. Richardson P, Mitsiades C, Colson K, Reilly E, McBride L, Chiao J, et al. Phase I trial of oral Vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced multiple myeloma. Leuk Lymphoma 2008; 49: 502-7
107. Khan N, Jeffers M, Kumar S, Hackett C, Boldog F, Khramtsov N, et al. Determination of the class and isoform selectivity of smallmolecule histone deacetylase inhibitors. Biochem J 2008; 409: 581-9
108. Gimsing P. Belinostat: A new broad acting antineoplastic histone deacetylase inhibitor. Expert Opin Investig Drugs 2009; 18: 501-8
109. Gimsing P, Hansen M, Knudsen LM, Knoblauch P, Christensen IJ, Ooi CE, et al. A phase I clinical trial of the histone deacetylase inhibitor belinostat in patients with advanced hematological neoplasia. Eur J Haematol 2008; 81: 170-6
110. Pohlman B, Advani R, Duvic M, Hymes KB, Intragumtornchai T, Lekhakula A, et al. Final results of a phase II trial of Belinostat (PXD101) in patients with recurrent or refractory peripheral or cutaneous T-cell lymphoma. Blood (ASH annual meeting abstract) 2009; 920 [Abstract]
111. Giles F, Fischer T, Cortes J, Garcia-Manero G, Beck J, Ravandi F, et al. A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clin Cancer Res 2006; 12: 4628-35
112. Leoni F, Fossati G, Lewis EC, Lee JK, Porro G, Pagani P, et al. The histone deacetylase inhibitor ITF2357 reduces production of proinflammatory cytokines in vitro and systemic inflammation in vivo. Mol Med 2005; 11: 1-15
113. Fournel M, Bonfils C, Hou Y, Yan PT, Trachy-Bourget MC, Kalita A, et al. MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo. Mol Cancer Ther 2008; 7: 759-68
114. Stimson L, Wood V, Khan O, Fotheringham S, La Thangue NB. HDAC inhibitorbased therapies and haematological malignancy. Ann Oncol 2009; 20: 1293-302
115. Hess-Stumpp H, Bracker TU, Henderson D, Politz O. MS-275, a potent orally available inhibitor of histone deacetylases - the development of an anti-cancer agent. Int J Biochem Cell Biol 2007; 39(7-8): 1388-405
116. Kummar S, Gutierrez M, Gardner ER, Donovan E, Hwang K, Chung EJ, et al. Phase I trial of MS-275, a histone deacetylase inhibitor, administered weekly in refractory solid tumors and lymphoid malignancies. Clin Cancer Res 2007; 13: 5411-7
117. Konstantinopoulos PA, Vandoros GP, Papavassiliou AG. FK228(Depsipeptide):a HDAC inhibitor with pleiotropic antitumor activities. Cancer Chemother Pharmacol 2006; 58: 711-5
118. Shigematsu N, Ueda H, Takase S, Tanaka H, Yamamoto K, Tada T. FR90122, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No-968.11 structure determination. J Antibiot (Tokyo) 1994; 74(3): 311-4
119. Byrd JC, Marcucci G, Parthun MR, Xiao JJ, Klisovic RB, Moran M, et al. A phase 1 and pharmacodynamic study of Depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. Blood 2005; 105: 959-67
120. Klimek VM, Fircanis S, Maslak P, Guernah I, Baum M, Wu N, et al. Tolerability, pharmacodynamics, and pharmacokinetics studies of Depsipeptide (Romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes. Clin Cancer Res 2008; 14: 1853 826-32
121. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2009/ucm189629.htm
122. Piekarz RL, Frye AR, Wright JJ, Steinberg SM, Liewehr DJ, Rosing DR, et al. Cardiac studies in patients treated with Depsipeptide, FK228, in a phase II trial for T-cell lymphoma. Clin Cancer Res 2006; 12: 3762-73
123. Shindoh N, Mori M, Terada Y, Oda K, Amino N, Kita A, et al. YM753, a novel histone deacetylase inhibitor, exhibits antitumoractivity with selective, sustained accumulation of acetylated histones in tumors in the WiDr xenograft model. Int J Oncol 2008; 32: 545-55
124. Göttlicher M, Minucci S, Zhu P, Krämer OH, Schimpf A, Giavara S, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 2001; 20(24): 6969-78
125. Tan J, Cang S, Ma Yu, Petrillo RL, Delong L. Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. J Hematol Oncol 2010; 3: 5
126. Chakravarty, P.K., Kuo, H., Matthews, J.M., Meinke, P.T. Inhibitors of histone deacetylase. US20080015190 (2008)
127. Belvedere, S., Methot, J.L., Miller, T.A., Witter, D.J., Yan, J. Histone deacetylase inhibitors. US20080015216 (2008)
128. Belvedere, S., Hamblett, C.L., Miller, T.A., Witter, D.J., Yan, J. Histone deacetylase inhibitors. US20080033015 (2008) & US20090118291 (2008)
129. Fertig, G., Herting, F., Koerner, M., Kubbies, M., Limberg, A., Reiff, U., Tibes, U. Thiophene hydroxamic acid derivatives and their use as HDAC inhibitors. US20080070976 (2008)
130. Belvedere, S., Miller, T.A., Witter, D.J. Inhibitors of histone deacetylase. US20080096920 (2008)
131. Bressi, J.C., Gangloff, A.R., Kwok, L. Histone deacetylase inhibitors. US20080108829 (2008), US20080114037 (2008), US20080119648 (2008), US20090105485 (2009), US20090111996 (2009)
132. Mcculloch, W., Piekarz, R.L., Bates, S.E. Deacetylase inhibitor therapy. US20080124403 (2008)
133. Moradei, O., Paquin, I., Leit, S., Frechette, S., Vaisburg, A., Besterman, J.M., T., Mallais, T. Inhibitors of histone deacetylase. US20080132459 (2008)
134. Anandan, S.K., Xiao, X., Patel, D.V., Ward, J.S. Inhibitors of histone deacetylase. US20080139535 (2008)
135. Sendzik, M. Acetylene derivatives as inhibitors of histone deacetylase. US20080139547 (2008)
136. Malecha, J., Noble, S., Hassig, C., Wash, P., Wiley, B., Lawrence, C., Hoffman, T., Bonnefous, C., Smith, N. Novel inhibitors of histone deacetylase for the treatment of disease. US20080194681 (2008)
137. Miller, T.A., Richon, V.M. Polymorphs of suberoylanilide hydroxamic acid. US20080194692 (2008), US20090042992 (2009)
138. Deziel, R., Leit, S., Beaulieu, P., Chantigny, Y.A., Mancuso, J., Tessier, P., Shapiro, G., Chesworth, R., Smil, D. Inhibitor of histone deacetylase. US20080207590 (2008)
139. Mink, S., Martin, E., Hentsch, B. Use of inhibitors of histone deacteylases in combination with compounds acting as nsaid for the therapy of human diseases. US20080207724 (2008)
140. Nakanishi, O., Tatamiya, T. Histone deacetylase inhibitor and use thereof. US20080213813 (2008)
141. Chakravarty, P.K., Colletti, S.L., Ingenito, R., Jones, P., Meinke, P.T., Muraglia, E., Petrocchi, A., Rowley, M., Scarpelli, R., Steinkuhler, C. Amide derivatives as inhibitors of histone deacetylase. US20080221157 (2008)
142. Frechette, S., Isakovic, L., Paquin, I., Roy, S., Moradei, O., Vaisburg, A. Inhibitors of histone deacetylase. US20080227826 (2008)
143. Van Emelen, K. Squaric acid derivatives as inhibitors of histone deacetylase. US20080255140 (2008)
144. Chakravarty, P.K., Colletti, S.L., Ingenito, R., Meinke, P.T., Petrocchi, A., Steinkuhler, C. Amide derivatives as inhibitors of histone deacetylase. US20080262035 (2008)
145. Cossio, M.F., Esteller, B.M., Zubia, O.A., Otaegui, A.D. Pyrrolic derivatives with histone deacetylase inhibitory activity. US20080262073 (2008)
146. Andrews, D.M., Stokes, E.S.E., Turner, A., Waring, M.J. Benzamide compounds useful as histone deacetylase inhibitors. US20080269294 (2008)
147. Lichenstein, H., Edwards, N., Ritchie, J., Petersen, K.D., Plumb, J. Histone deacetylase (HDAC) inhibitors (Pxd101) for the treatment of cancer alone or in combination with chemotherapeutic agent. US20080274120 (2008)
148. Richon, V.C., Judy H., Miller, T.A., Bacopoulos, N.G., Paradise, C.M. Methods of treating cancer with HDAC inhibitors. US20080227862 (2008)
149. Grigg, R., Cook, A. Inhibitors of histone deacetylase. US20080234254 (2008)
150. Bacopoulos, N.G., Chiao, J.H., Miller, T. A., Paradise, C.M., Richon, V.M., Kelly, W.K. Methods of treating cancer with HDAC inhibitors. US20080249179 (2008)
151. Kushner, P., Goldfine, I.D., Hodges-Gallagher, L., Valentine, C.D. Small molecule potentiator of hormonal therapy for breast cancer. US20080085874 (2008)
152. Bacopoulos, N.G., Chiao, J.H., Miller, T.A., Paradise, C.M., Richon, V. M. Methods of treating cancer with HDAC inhibitors. US20090012175 (2009)
153. Angibaud, P.R., Pilatte, I.N.C., Roux, B., Arts, J. Aminophenyl derivatives as Novel Inhibitors of histone deacetylase. US20090018152 (2009)
154. Miller, T.A., Witter, David J. Belvedere, S. Histone deacetylase inhibitor prodrugs. US20090023786 (2009)
155. Magda, D., Wang, Z. Thiohydroxamates as inhibitors of histone deacetylase. US20090023798 (2009)
156. Brodie, A. Njar, V., Sabnis, G., Gediya, L. HDAC Inhibitors and hormone targeted drugs for the treatment of cancer. US20090048156 (2009)
157. Attenni, B., Ferrigno, F., Jones, P., Ingenito, R., Kinzel, O., Llauger Bufi, L., Ontoria, J.M. Pescatore, G., Rowley, M., Scarpelli, R., Schultz, C. Heterocycle derivatives as histone deacetylase (HDAC) inhibitors. US20090048228 (2009)
158. Jones, P. Amino acid derivatives as histone deacetylase (HDAC) inhibitors.US20090054448 (2009)
159. Hubbs, J.L., Kattar, S., Methot, J., Miller, T., Siliphaivanh, P., Stanton, M., Wilson, K., Witter, D.J. Benzothiophene hydroxamic acid derivatives. US20090069391 (2009)
160. Ferrigno, F., Jones, P., Muraglia, E., Ontoria, J.M., Scarpelli, R., Schultz-fademrecht, C. Thiophene and thiazole substituted trifluoroethanone derivatives as histone deacetylase (HDAC) inhibitors.US20090076101 (2009)
161. Huang, C., Chen, C., Huang, W., Huang, C., Chi, L., You, C. Compounds for the inhibition of histone deacetylase. US20090076130 (2009)
162. Hubbs, J.L., Mampreian, D.M, Methot, J.L., Miller, T.A., Otte, K. M., Siliphaivanh, P., Sloman, D.L., Stanton, M.G., Wilson, K.J., Witter, D.J. Benzothiophene derivatives. US20090082308 (2009)
163. Maurer, A.B., Hoevelmann, S., Martin, E., Hentsch, B., Gassen, M., Kraus, J., Krauss, R., Vincek, A. Novel compounds as histone deacetylase inhibitors. US20090088478 (2009)
164. Buggy, J.J., Balasubramanian, S. Methods for determining cancer resistance to histone deacetylase inhibitors. US20090123374 (2009)
165. Srinivas, V.A.S.S., Balan, U.K., Punthalir, N.S., Velmurugan, R.S., Rajagopal, S. Reddy, G.O., Kachhadia, V. Stilbene like compounds as novel HDAC Inhibitors. US20090136431 (2009)
166. Yu, Q. Methods for assessing suitability of cancer patients for treatment with histone deacetylase inhibitors. US20090137451 (2009)
167. Chen, C., Lu, Q. ZN2+ Chelating motif-tethered short-chain fatty acids as a novel class of histone deacetylase inhibitors. US20090137679 (2009)
168. Ferrigno, F., Jones, P., Muraglia, E., Ontoria, J.M., Scarpelli, R. Thiophene and thiazole substituted trifluoroethanone derivatives as histone deacetylase (HDAC) inhibitors. US20090156591 (2009)
169. Jones, P., Ontoria O., J.M. Heterocycle substituted amide and sulfur amide derivatives as histone deacetylase (HDAC) inhibitors. US20090156619 (2009)
170. Tessier, P., Leit, S., Smil, D., Deziel, R., Ajamian, A., Chantigny, Y.A., Dominguez, C. Inhibitors of histone deacetylase. US20090181943 (2009)
171. Delorme, D., Woo, S.H., Vaisburg, A. Inhibitors of histone deacetylase. US20090181971 (2009)
172. Casero, R.A., Woster, P.M., Varghese, S. Histone deacetylase inhibitors. US20090182019 (2009)
173. Mazitschek, R., Kwiatkowski, N.P., Bradner, J.E. Histone deacetylase and tubulin deacetylase inhibitors.US20090209590 (2009)
174. Chan, K.K., Xiao, J. Antitumor agents. US20090221473 (2009)
175. Heidebrecht, R., Methot, J., Mampreian, D., Miller, T., Siliphaivanh, P. Disubstituted aniline compounds. US20090221669 (2009)
176. Frankel, S.R., Deutsch, P.J., Randolph, S., Fine, B. Methods of using SAHA and bortezomib for treating cancer. US20090247549 (2009)
177. Yu, Q. Methods for assessing suitability of cancer patients for treatment with histone deacetylase inhibitors. US20090318329 (2009)
178. Methot, J., Miller, T.A., Witter, D.J. Benzothiophene hydroxamic acid derivatives with carbamate, urea, amide and sulfonamide substitutions. US20090318541 (2009)
179. Campbell, J.M., Bunce, C., Gommersall, L., Peehl, D. Cancer therapy and medicaments therefor. US20090105343 (2009)
180. Filocamo, G., Steinkuhler, C. Inhibitors of mammalian HDAC 11 useful for treating hdac 11 mediated disorders. US20090253769 (2009)
181. Close, J., Heidebrecht, R.W., Kattar, S., Miller, T.A., Sloman, D., Stanton, M.G., Tempest, P., Witter, D.J. Histone deacetylase inhibitors with aryl-pyrazolyl-motifs. US20090291965 (2009)
182. Maier, T., Beckers, T., Hummel, R., Feth, M., Müller, M., Bär, T. Sulphonylpyrrole hydrochloride salts as histone deacetylases inhibitors. US20090297473 (2009)
183. Davidson, A.H., Patel, S.R., Moffat, D.F.C. Hydroxamic acid derivatives as inhibitors of HDAC enzymatic activity. US20090298924 (2009)
184. Gomez, V.J.A., Dominguez, S.J.F. Derivatives of benzo[d] isothiazoles as histones deacetylase inhibitors. US20090312377 (2009)
185. Stokes, E.S.E., Carr, G. N-(2-aminiphenyl)-4-(5-((ethylamino) methyl)-1,2-thiazol-2-yl) benzamide and n-(2-aminophenyl)-4-(5- ((isopropylamino)methyl)-1,2-thiazol-2-yl) benzamide as hdac inhibitors. US20090312556 (2009)
186. Bible, K.C., Isham, C.R., Xu, R., Tibodeau, J.D. Methods and compositions for treating cancer. US20090264421 (2009)
187. Brodie, A., Njar, V., Sabnis, G., Gediya, L. HDAC Inhibitors and hormone targeted drugs for the treatment of cancer. US20090048156 (2009)
188. Shultz, M. Organic compounds. US20100008923 (2010)
189. Van Emelen, K. New compounds with HDAC inhibitor activity. US20100009988 (2010)
190. Venkataramani, C. Compounds having histone deacetylase and/orcyclin-dependent kinase (CDK) inhibitory activity. US20100009990 (2010)
191. Van Emelen, K., Gustaaf, M., Verdonck, C., Van Brandt, S.F.A, Angibaud, P.R., Meerpoel, A., Dyatkin, B. New compounds with HDAC inhibitor activity. US20100010004 (2010)
192. White, J., Gleason, J., Tavera Mendoza, L.E., Quach, T. Hybrid molecole having mixed vitamin D receptor agonism and histone deacetylase inhibitory properties. US20100016435 (2010)
193. Melvin, L.S., Graupe, M., Venkataramani, C. Cycloalkylidene and heterocycloalkylidene inibitor compounds. US20100022543 (2010)
194. Zaknoen, S., Ma Woo, M., Versace, R.W., Pisano, C., Vesci, L. Combinations of therapeutic agents for treating cancer. US20100028338 (2010)
195. Yoneda, S., Fujisawa, K., Watanabe, K., Fujikaw, J., Shimazaki, A., Kirihara, T., Tajima, H. Intraocular pressure-lowering agent comprising compounds having histone deacetylase inhibitor effect as active ingredient.US20100056522 (2010)
196. Bradner, J.E., Mazitschck, R. Hitone deacetylase inhibitors. US20100056588 (2010)
197. Ronen, S.M., Gelovani, J.G., Bornmann, W.G., Pang, J., Pal, A., Tong, W.P., Paz, A., Tong, W.P., Maxwell, D.S., Sankaranarayanapillai, M. Detection of histone deacetylase ihibition. US20100062465 (2010)
198. Wang H, Dymock BW. New patented histone deacetylase inhibitors. Expert Opin Ther Pat 2010; 12:1727-57
199. Sgouros, G., Richon, V.M., Marks, Paul A., Rifkind, R.A. Use of histone deacetylase inhibitors in combination with radiation for the treatment of cancer. US20090054720 (2009)
200. Bunn, P., Witta, S., Richon, V.M., Frankel, S.R., Deutsch, P.J., Randolph, S. Method of using SAHA and Erlotinib for treating cancer. US20080221138 (2008)
201. Pluda, J., Frankel, S.R., Richon, V.M., Averbuch, S., Chiao, J.H. Method of treating cancers with SAHA and Pemetrexed. US20080269182 (2008)
202. Richon, V.M., Frankel, S.R. Combination methods fo saha and targretin for treating cancer. US20090227674 (2009)
203. Ordentlich, P., Horobin, J., Whitehouse, M.J., Rees, M. Combination of ERA+ ligands and histone deacetylase inhibitors for the treatment of cancer. US20080242648 (2008)
204. Arts, J., Hellemans, Peter W.J., Janicot, M.M.F., Page, M.J. Histone deacetylase inhibitors with combined activity on class-I and class-IIB histone deacetylases in combination with proteasome inhibitors. US20090312284 (2009)
205. Arts, J., Hellemans, Peter W.J., Janicot, M.M.F., Page, M.J. Combinations of class-I specific histone deacetylase inhibitors with proteasome inhibitors. US20090270419 (2009)
206. Gore, L., Deryckere, D. Combinations of HDAC inhibitors and proteasome inhibitors. US20090131367 (2009)
207. Witta, S.E., Bunn, P.A., Drabkin, H.A. Gemmill, R.M., Chan, D.C. Histone deacetylase inhibitors sensitize cancer cells to epidermal growth factor inhibitors. US20080234265 (2008), US20080182865 (2008)
208. Dimartino, J.F. Compositions and methods for treating diseases through inhibition of DNA methylation and histone deacetylase. US20080108559 (2008)
209. Yu, Q. Methods for assessing suitability of cancer patients for treatment with histone deacetylase inhibitors. US20090318329 (2009)
210. Burk, K., Ordentlich, P., Goodenow, R. Administration of an Inhibitor of HDAC and an mTOR Inhibitor. US20090149511 (2009)
211. Bernards, R., Epping, M., Wang, L. Combined use of prame inhibitors and HDAC inhibitors. US20080119424 (2008)
212. Lichenstein, H., Jeffers, M., Qian, X., Sehested, M., Petersen, K.D., Ritchie, J. Combination therapies using HDAC inhibitors. US20080213399 (2008)
213. Green, S., Frame, S., Fleming, I. Combination of roscovitine and a HDAC inhibitor to treat proliferative diseases. US20090306098 (2009)
214. Ksander, G.M., Shetty, S.S. Combination of organic compounds. US20090312311 (2009)
215. Ferrara FF, Fazi F, Bianchini A, Padula F, Gelmetti V, Minucci S, et al. Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia. Cancer Res 2001; 61: 2-7
216. Bemis, J., Disch, J.S., Jirousek, M., Lunsmann, W.J., Ng, P.Y., Vu, C.B. Sirt modulating compounds. US20090012080 (2009)
217. Milburn, M., Milne, J., Bemis, J., Nunes, J.J., Xie, R., Normington, K.D. Acridine and quinoline derivatives as sirtuin modulators.US20090069301 (2009)
218. Nunes, J.J., Milne, J., Bemis, J., Xie, R., Vu, C.B., Ng, P.Y., Disch, J.S. Sirtuin modulating compounds.US20090099170 (2009)
219. Bemis, J., Disch, J.S., Ng, P.Y., Oalmann, C., Perni, R.B., Vu, C.B. Sirtuin modulating compounds. US20090105246 (2009)
220. Hamblett, C., Mampreian, D.M., Methot, J.L., Miller, T., Sloman, D.L., Stanton, M.G., Wilson, K. Substituted nicotinamide compounds. US20090105264 (2009)
221. Sinclair, D.A., Mai, A. Sirtuin inhibiting compounds. US20090137681 (2009)
222. Milburn, M., Milne, J., Bemis, J., Nunes, Joseph J., Xie, R., Nomington, K.D.,Vu, C.B. Fused heterocyclic compounds and their use as sirtuin modulators. US20090143376 (2009)
223. Milburn, M., Milne, J., Bemis, J., Nunes, J.J., Xie, R., Normington, K.D., Vu, C.B. N-Phenyl benzamide derivatives as sirtuin modulators.US20090163476 (2009)
224. Lain S, Hollick JJ, Campbell J, Staples OD, Higgins M, Aoubala M, et al. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 2008; 5: 454-63.