Reversible inhibitors of LSD1 as therapeutic agents in acute myeloid leukemia: Clinical significance and progress to date

Medicinal Research Reviews

Volumn 35, Issue 3, 2015, Pages 586-618

  Mould, Daniel P ^a   McGonagle, Alison E ^a   Wiseman, Daniel H ^a   Williams, Emma L ^a   Jordan, Allan M ^a  

^a UNIVERSITY OF MANCHESTER   (United Kingdom)

Author keywords

Drug discovery; Enzyme inhibition; Epigenetics; Leukemia; Oncology

Indexed keywords

AMIDOXIME; AMINOTHIAZOLE; ANTINEOPLASTIC AGENT; CHROMONE DERIVATIVE; DITHIOCARBAMIC ACID; GSK 354; HYDRAZIDE DERIVATIVE; NAMOLINE; PEPTIDE; PHENYL OXAZOLE; POLYAMINE; RETINOBLASTOMA BINDING PROTEIN 1; TRANYLCYPROMINE DERIVATIVE; UNCLASSIFIED DRUG; HISTONE DEMETHYLASE; LYSINE;

ACUTE GRANULOCYTIC LEUKEMIA; ARTICLE; CANCER GENETICS; CANCER INHIBITION; CANCER STEM CELL; CELL PROLIFERATION; CHEMICAL ANALYSIS; DRUG DEVELOPMENT; DRUG STRUCTURE; EPIGENETICS; GENETIC DISORDER; HUMAN; IC50; NONHUMAN; PROTEIN ANALYSIS; PROTEIN FUNCTION; PROTEIN STRUCTURE; ANIMAL; CHEMISTRY; DRUG DESIGN; DRUG SCREENING; GENE EXPRESSION REGULATION; GENETIC EPIGENESIS; LEUKEMIA, MYELOID, ACUTE; MOUSE; TREATMENT OUTCOME;

ANIMALS; ANTINEOPLASTIC AGENTS; DRUG DESIGN; DRUG SCREENING ASSAYS, ANTITUMOR; EPIGENESIS, GENETIC; GENE EXPRESSION REGULATION, LEUKEMIC; HISTONE DEMETHYLASES; HUMANS; INHIBITORY CONCENTRATION 50; LEUKEMIA, MYELOID, ACUTE; LYSINE; MICE; POLYAMINES; TREATMENT OUTCOME;

EID: 84926475466     PISSN: 01986325     EISSN: 10981128     Source Type: Journal    
DOI: 10.1002/med.21334     Document Type: Article

References (136)

1. Kumar CC. Genetic abnormalities and challenges in the treatment of acute myeloid leukemia. Gene Cancer 2011;2:95-107.
2. Ganzel C, Becker J, Mintz PD, Lazarus HM, Rowe JM. Hyperleukocytosis, leukostasis and leukapheresis: Practice management. Blood Rev 2012;26:117-122.
3. Estey E, Döhner H. Acute myeloid leukaemia. Lancet 2006;368:1894-1907.
4. Hromas R, Shopnick R, Jumean HG, Bowers C, Varella-Garcia M, Richkind K. A novel syndrome of radiation-associated acute myeloid leukemia involving AML1 gene translocations. Blood 2000;95:4011-4013.
5. Wong O. Risk of acute myeloid leukaemia and multiple myeloma in workers exposed to benzene. Occup Environ Med 1995;52:380-384.
6. Wandt H, Schäkel U, Kroschinsky F, Prange-Krex G, Mohr B, Thiede C, Pascheberg U, Soucek S, Schaich M, Ehninger G. MLD according to the WHO classification in AML has no correlation with age and no independent prognostic relevance as analyzed in 1766 patients. Blood 2008;111:1855-1861.
7. Godley LA, Larson RA. Therapy-related myeloid leukemia. Semin Oncol 2008;35:418-429.
8. Bennett JM, Catovsky D, Daniel M-T, Flandrin G, Galton DAG, Gralnick HR, Sultan C. Proposals for the classification of the acute leukaemias French-American-British (FAB) co-operative group. Br J Haematol 1976;33:451-458.
9. Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH, Naoe T, Lengfelder E, Büchner T, Döhner H, Burnett AK, Lo-Coco F. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009;113:1875-1891.
10. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellström-Lindberg E, Tefferi A, Bloomfield CD. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes. Blood 2009;114:937-951.
11. Bishop JF, Matthews JP, Young G, Szer J, Joshua DE, Dodds A, Laidlaw CR, Cobcroft R, Herrman R, Ma D, Page FJ. The influence of induction chemotherapy dose and dose intensity on the duration of remission in acute myeloid leukemia. Leuk Lymphoma 1994;15:79-84.
12. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, Rees J, Hann I, Stevens R, Burnett A, Goldstone A. The importance of diagnostic cytogenetics on outcome in AML: Analysis of 1, 612 patients entered into the MRC AML 10 trial. Blood 1998;92:2322-2333.
13. Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: Results of the MRC AML15 trial. J Clin Oncol 2011;29:369-377.
14. Holowiecki J, Grosicki S, Giebel S, Robak T, Kyrcz-Krzemien S, Kuliczkowski K, Skotnicki AB, Hellmann A, Sulek K, Dmoszynska A. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: A multicenter, randomized phase III study. J Clin Oncol 2012;30:2441-2448.
15. Appelbaum FR. Haematological cancer: The rule of three in AML induction-Is cladribine the answer? Nat Rev Clin Oncol 2012;9:376-377.
16. Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Löwenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD. Revised recommendations of the international working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 2003;21:4642-4649.
17. Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P, Omura GA, Moore JO, McIntyre OR, Frei E. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 1994;331:896-903.
18. Cornelissen JJ, Gratwohl A, Schlenk RF, Sierra J, Bornhäuser M, Juliusson G, Råcil Z, Rowe JM, Russell N, Mohty M. The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: An integrated-risk adapted approach. Nat Rev Clin Oncol 2012;9:579-590.
19. Hämäläinen S, Kuittinen T, Matinlauri I, Nousiainen T, Koivula I, Jantunen E. Neutropenic fever and severe sepsis in adult acute myeloid leukemia (AML) patients receiving intensive chemotherapy: Causes and consequences. Leuk Lymphoma 2008;49:495-501.
20. Mandelli F, Vignetti M, Suciu S, Stasi R, Petti M-C, Meloni G, Muus P, Marmont F, Marie J-P, Labar B. Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: The EORTC and GIMEMA Groups Study AML-10. J Clin Oncol 2009;27:5397-5403.
21. Appelbaum FR, Gundacker H, Head DR, Slovak ML, Willman CL, Godwin JE, Anderson JE, Petersdorf SH. Age and acute myeloid leukemia. Blood 2006;107:3481-3485.
22. Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, Dombret H, Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Löwenberg B, Bloomfield CD. Diagnosis and management of acute myeloid leukemia in adults: Recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010;115:453-474.
23. Wheatley K, Brookes CL, Howman AJ, Goldstone AH, Milligan DW, Prentice AG, Moorman AV, Burnett AK, on behalf of the United Kingdom National Cancer Research Institute Haematological Oncology Clinical Studies G, Acute Myeloid Leukaemia S. Prognostic factor analysis of the survival of elderly patients with AML in the MRC AML11 and LRF AML14 trials. Br J Haematol 2009;145:598-605.
24. Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U, Sanz G, List AF, Gore S, Seymour JF, Dombret H, Backstrom J, Zimmerman L, McKenzie D, Beach CL, Silverman LR. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 2010;28:562-569.
25. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997;3:730-737.
26. Wiseman DH, Greystoke BF, Somervaille TCP. The variety of leukemic stem cells in myeloid malignancy. Oncogene 2014;33:3091-3098.
27. Mrózek K, Heinonen K, Bloomfield CD. Clinical importance of cytogenetics in acute myeloid leukaemia. Best Pract Res Clin Haematol 2001;14:19-47.
28. Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, Wheatley K, Harrison CJ, Burnett AK, Group obotNCRIALW. Refinement of cytogenetic classification in acute myeloid leukemia: Determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010;116:354-365.
29. Boissel N, Renneville A, Biggio V, Philippe N, Thomas X, Cayuela J-M, Terre C, Tigaud I, Castaigne S, Raffoux E. Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. Blood 2005;106:3618-3620.
30. Higuchi M, O'Brien D, Kumaravelu P, Lenny N, Yeoh E-J, Downing JR. Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia. Cancer Cell 2002;1:63-74.
31. Kelly LM, Gilliland DG. Genetics of myeloid leukemias. Annu Rev Genomics Hum Genet 2002;3:179-198.
32. Ley TJ, Mardis ER, Ding L, Fulton B, McLellan MD, Chen K, Dooling D, Dunford-Shore BH, McGrath S, Hickenbotham M, Cook L, Abbott R, Larson DE, Koboldt DC, Pohl C, Smith S, Hawkins A, Abbott S, Locke D, Hillier LW, Miner T, Fulton L, Magrini V, Wylie T, Glasscock J, Conyers J, Sander N, Shi X, Osborne JR, Minx P, Gordon D, Chinwalla A, Zhao Y, Ries RE, Payton JE, Westervelt P, Tomasson MH, Watson M, Baty J, Ivanovich J, Heath S, Shannon WD, Nagarajan R, Walter MJ, Link DC, Graubert TA, DiPersio JF, Wilson RK. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature 2008;456:66-72.
33. Riva L, Luzi L, Pelicci PG. Genomics of acute myeloid leukemia: The next generation. Front Oncol 2012;2:40.
34. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013;368:2059-2074.
35. Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes Dev 2009;23:781-783.
36. Suzuki MM, Bird A. DNA methylation landscapes: Provocative insights from epigenomics. Nat Rev Genet 2008;9:465-476.
37. Saha A, Wittmeyer J, Cairns BR. Chromatin remodelling: The industrial revolution of DNA around histones. Nat Rev Mol Cell Biol 2006;7:437-447.
38. Strahl BD, Allis CD. The language of covalent histone modifications. Nature 2000;403:41-45.
39. Rice JC, Briggs SD, Ueberheide B, Barber CM, Shabanowitz J, Hunt DF, Shinkai Y, Allis CD. Histone methyltransferases direct different degrees of methylation to define distinct chromatin domains. Mol Cell 2003;12:1591-1598.
40. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis 2010;31:27-36.
41. Slany RK. The molecular biology of mixed lineage leukemia. Haematologica 2009;94:984-993.
42. Delhommeau F, Dupont S, Valle VD, James C, Trannoy S, Massé A, Kosmider O, Le Couedic J-P, Robert F, Alberdi A, Lécluse Y, Plo I, Dreyfus FJ, Marzac C, Casadevall N, Lacombe C, Romana SP, Dessen P, Soulier J, Viguié F, Fontenay M, Vainchenker W, Bernard OA. Mutation in TET2 in myeloid cancers. N Engl J Med 2009;360:2289-2301.
43. Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, Kandoth C, Payton JE, Baty J, Welch J, Harris CC, Lichti CF, Townsend RR, Fulton RS, Dooling DJ, Koboldt DC, Schmidt H, Zhang Q, Osborne JR, Lin L, O'Laughlin M, McMichael JF, Delehaunty KD, McGrath SD, Fulton LA, Magrini VJ, Vickery TL, Hundal J, Cook LL, Conyers JJ, Swift GW, Reed JP, Alldredge PA, Wylie T, Walker J, Kalicki J, Watson MA, Heath S, Shannon WD, Varghese N, Nagarajan R, Westervelt P, Tomasson MH, Link DC, Graubert TA, DiPersio JF, Mardis ER, Wilson RK. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010;363:2424-2433.
44. Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV, Waghorn K, Zoi K, Ross FM, Reiter A, Hochhaus A, Drexler HG, Duncombe A, Cervantes F, Oscier D, Boultwood J, Grand FH, Cross NCP. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet 2010;42:722-726.
45. Gelsi-Boyer V, Trouplin V, Adélaïde J, Bonansea J, Cervera N, Carbuccia N, Lagarde A, Prebet T, Nezri M, Sainty D, Olschwang S, Xerri L, Chaffanet M, Mozziconacci M-J, Vey N, Birnbaum D. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol 2009;145:788-800.
46. Bernt KM, Zhu N, Sinha AU, Vempati S, Faber J, Krivtsov AV, Feng Z, Punt N, Daigle A, Bullinger L, Pollock RM, Richon VM, Kung AL, Armstrong SA. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 2011;20:66-78.
47. Guenther MG, Lawton LN, Rozovskaia T, Frampton GM, Levine SS, Volkert TL, Croce CM, Nakamura T, Canaani E, Young RA. Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia. Genes Dev 2008;22:3403-3408.
48. Yamazaki J, Estecio MR, Lu Y, Long H, Malouf GG, Graber D, Huo Y, Ramagli L, Liang S, Kornblau SM. The epigenome of AML stem and progenitor cells. Epigenetics 2012;8:92-104.
49. Figueroa ME, Lugthart S, Li Y, Erpelinck-Verschueren C, Deng X, Christos PJ, Schifano E, Booth J, van Putten W, Skrabanek L. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 2010;17:13-27.
50. Akalin A, Garrett-Bakelman FE, Kormaksson M, Busuttil J, Zhang L, Khrebtukova I, Milne TA, Huang Y, Biswas D, Hess JL. Base-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia. PLoS Genet 2012;8:e1002781.
51. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrom J, Zimmerman L, McKenzie D, Beach CL, Silverman LR. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: A randomised, open-label, phase III study. Lancet Oncol 2009;10:223-232.
52. Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, Gau J-P, Chou W-C, Buckstein R, Cermak J. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol 2012;30:2670-2677.
53. Garcia-Manero G, Tambaro FP, Bekele NB, Yang H, Ravandi F, Jabbour E, Borthakur G, Kadia TM, Konopleva MY, Faderl S. Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome. J Clin Oncol 2012;30:2204-2210.
54. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 2004;119:941-953.
55. Metzger E, Wissmann M, Yin N, Muller JM, Schneider R, Peters AHFM, Gunther T, Buettner R, Schule R. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 2005;437:436-439.
56. Cai C, He Housheng H, Chen S, Coleman I, Wang H, Fang Z, Chen S, Nelson Peter S, Liu XS, Brown M, Balk Steven P. Androgen receptor gene expression in prostate cancer is directly suppressed by the androgen receptor through recruitment of lysine-specific demethylase 1. Cancer Cell 2011;20:457-471.
57. Bannister AJ, Schneider R, Kouzarides T. Histone methylation: Dynamic or static? Cell 2002;109:801-806.
58. Forneris F, Binda C, Battaglioli E, Mattevi A. LSD1: Oxidative chemistry for multifaceted functions in chromatin regulation. Trends Biochem Sci 2008;33:181-189.
59. Da G, Lenkart J, Zhao K, Shiekhattar R, Cairns BR, Marmorstein R. Structure and function of the SWIRM domain, a conserved protein module found in chromatin regulatory complexes. Proc Natl Acad Sci USA 2006;103:2057-2062.
60. Wang Y, Zhang H, Chen Y, Sun Y, Yang F, Yu W, Liang J, Sun L, Yang X, Shi L, Li R, Li Y, Zhang Y, Li Q, Yi X, Shang Y. LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell 2009;138:660-672.
61. Forneris F, Binda C, Adamo A, Battaglioli E, Mattevi A. Structural basis of LSD1-CoREST selectivity in histone H3 recognition. J Biol Chem 2007;282:20070-20074.
62. Chen Y, Yang Y, Wang F, Wan K, Yamane K, Zhang Y, Lei M. Crystal structure of human histone lysine-specific demethylase 1 (LSD1). Proc Natl Acad Sci USA 2006;103:13956-13961.
63. Stavropoulos P, Blobel G, Hoelz A. Crystal structure and mechanism of human lysine-specific demethylase-1. Nat Struct Mol Biol 2006;13:626-632.
64. Shi Y-J, Matson C, Lan F, Iwase S, Baba T, Shi Y. Regulation of LSD1 histone demethylase activity by its associated factors. Mol Cell 2005;19:857-864.
65. Robertson JC, Hurley NC, Tortorici M, Ciossani G, Borrello MT, Vellore NA, Ganesan A, Mattevi A, Baron R. Expanding the druggable space of the LSD1/CoREST epigenetic target: New potential binding regions for drug-like molecules, peptides, protein partners, and chromatin. PLoS Comput Biol 2013;9:e1003158.
66. Kurtz KA, Rishavy MA, Cleland WW, Fitzpatrick PF. Nitrogen isotope effects as probes of the mechanism of D-amino acid oxidase. J Am Chem Soc 2000;122:12896-12897.
67. Edmondson DE, Binda C, Mattevi A. Structural insights into the mechanism of amine oxidation by monoamine oxidases A and B. Arch Biochem Biophys 2007;464:269-276.
68. Silverman RB. Radical ideas about monoamine oxidase. Acc Chem Res 1995;28:335-342.
69. Kong X, Ouyang S, Liang Z, Lu J, Chen L, Shen B, Li D, Zheng M, Li KK, Luo C, Jiang H. Catalytic mechanism investigation of lysine-specific demethylase 1 (LSD1): A computational study. PLoS One 2011;6:e25444.
70. Karasulu B, Patil M, Thiel W. Amine oxidation mediated by lysine-specific demethylase 1: Quantum mechanics/molecular mechanics insights into mechanism and role of lysine 661. J Am Chem Soc 2013;135:13400-13413.
71. Klose RJ, Kallin EM, Zhang Y. JmjC-domain-containing proteins and histone demethylation. Nat Rev Genet 2006;7:715-727.
72. Martin C, Zhang Y. The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol 2005;6:838-849.
73. Barski A, Cuddapah S, Cui K, Roh T-Y, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K. High-resolution profiling of histone methylations in the human genome. Cell 2007;129:823-837.
74. Zhang Y, Reinberg D. Transcription regulation by histone methylation: Interplay between different covalent modifications of the core histone tails. Genes Dev 2001;15:2343-2360.
75. Okitsu CY, Hsieh C-L. DNA methylation dictates histone H3K4 methylation. Mol Cell Biol 2007;27:2746-2757.
76. Metzger E, Imhof A, Patel D, Kahl P, Hoffmeyer K, Friedrichs N, Müller JM, Greschik H, Kirfel J, Ji S, Kunowska N, Beisenherz-Huss C, Günther T, Buettner R, Schüle R. Phosphorylation of histone H3T6 by PKCbeta(I) controls demethylation at histone H3K4. Nature 2010;464:792-796.
77. Forneris F, Binda C, Vanoni MA, Mattevi A, Battaglioli E. Histone demethylation catalysed by LSD1 is a flavin-dependent oxidative process. FEBS Lett 2005;579:2203-2207.
78. Yang M, Gocke CB, Luo X, Borek D, Tomchick DR, Machius M, Otwinowski Z, Yu H. Structural basis for CoREST-dependent demethylation of nucleosomes by the human LSD1 histone demethylase. Mol Cell 2006;23:377-387.
79. Baron R, Vellore NA. LSD1/CoREST is an allosteric nanoscale clamp regulated by H3-histone-tail molecular recognition. Proc Natl Acad Sci USA 2012;109:12509-12514.
80. Andrés ME, Burger C, Peral-Rubio MJ, Battaglioli E, Anderson ME, Grimes J, Dallman J, Ballas N, Mandel G. CoREST: A functional corepressor required for regulation of neural-specific gene expression. Proc Natl Acad Sci USA 1999;96:9873-9878.
81. Wang Y, Zhang H, Chen Y, Sun Y, Yang F, Yu W, Liang J, Sun L, Yang X, Shi L, Li R, Li Y, Zhang Y, Li Q, Yi X, Shang Y. LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell 2009;138:660-672.
82. Shi Y, Sawada J-I, Sui G, Affar EB, Whetstine JR, Lan F, Ogawa H, Luke MP-S, Nakatani Y, Shi Y. Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature 2003;422:735-738.
83. Harris WJ, Huang X, Lynch JT, Spencer GJ, Hitchin JR, Li Y, Ciceri F, Blaser JG, Greystoke BF, Jordan AM, Miller CJ, Ogilvie DJ, Somervaille TCP. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell 2012;21:473-487.
84. Schmidt DMZ, McCafferty DG. Trans-2-phenylcyclopropylamine is a mechanism-based inactivator of the histone demethylase LSD1. Biochemistry 2007;46:4408-4416.
85. Schenk T, Chen WC, Gollner S, Howell L, Jin L, Hebestreit K, Klein H-U, Popescu AC, Burnett A, Mills K, Casero RA, Marton L, Woster P, Minden MD, Dugas M, Wang JCY, Dick JE, Muller-Tidow C, Petrie K, Zelent A. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med 2012;18:605-611.
86. Lee SW, Cho YS, Na JM, Park UH, Kang M, Kim EJ, Um SJ. ASXL1 represses retinoic acid receptor-mediated transcription through associating with HP1 and LSD1. J Biol Chem 2010;285:18-29.
87. Guibourt N, Ortega Munoz A, Castro-Palomino LJ. Phenylcyclopropylamine derivatives and their medical use. Patent WO 2010/084160 A1, Oryzon Genomics S.A., 2010.
88. Lynch JT, Harris WJ, Somervaille TC. LSD1 inhibition: A therapeutic strategy in cancer? Expert Opin Ther Targets 2012;16:1239-1249.
89. Wang J, Scully K, Zhu X, Cai L, Zhang J, Prefontaine GG, Krones A, Ohgi KA, Zhu P, Garcia-Bassets I, Liu F, Taylor H, Lozach J, Jayes FL, Korach KS, Glass CK, Fu X-D, Rosenfeld MG. Opposing LSD1 complexes function in developmental gene activation and repression programmes. Nature 2007;446:882-887.
90. Sprüssel A, Schulte JH, Weber S, Necke M, Händschke K, Thor T, Pajtler KW, Schramm A, König K, Diehl L, Mestdagh P, Vandesompele J, Speleman F, Jastrow H, Heukamp LC, Schüle R, Dührsen U, Buettner R, Eggert A, Göthert JR. Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation. Leukemia 2012;26:2039-2051.
91. Liu L, Souto J, Liao W, Jiang Y, Li Y, Nishinakamura R, Huang S, Rosengart T, Yang VW, Schuster M, Ma Y, Yang J. Histone lysine-specific demethylase 1 (LSD1) protein is involved in Sal-like protein 4 (SALL4)-mediated transcriptional repression in hematopoietic stem cells. J Biol Chem 2013;288:34719-34728
92. Hojfeldt JW, Agger K, Helin K. Histone lysine demethylases as targets for anticancer therapy. Nat Rev Drug Discov 2013;12:917-930.
93. Khan MNA, Suzuki T, Miyata N. An overview of phenylcyclopropylamine derivatives: Biochemical and biological significance and recent developments. Med Res Rev 2013;33:873-910.
94. Culhane JC, Cole PA. LSD1 and the chemistry of histone demethylation. Curr Opin Chem Bio 2007;11:561-568.
95. Mimasu S, Sengoku T, Fukuzawa S, Umehara T, Yokoyama S. Crystal structure of histone demethylase LSD1 and tranylcypromine at 2.25Å. Biochem Biophys Res Commun 2008;366:15-22.
96. Ortega Munoz A, Laria JC-P, Fyfe MCT. Lysine specific demethylase-1 inhibitors and their use. Patent US 8722743 B2, Oryzon Genomics S.A., 2014.
97. Ortega Munoz A, Laria JC-P, Fyfe MCT. Lysine specific demethylase-1 inhibitors and their use. Patent US 2013/0090386 A1, Oryzon Genomics S.A., 2013.
98. Cartwright H. Roche partners with Oryzon Genomics and Spero Therapeutics. PharmaDeals Rev 2014;2014;5:5.
99. Johnson N, Kasparec J, Miller W, Rouse M, Suarez D, Tian X. Cyclopropylamines as LSD1 inhibitors. Patent WO 2012/135113 A3, GlaxoSmithKline, 2014.
100. Tomita N, Kajii S, Cary DR, Tomita D, Imamura S, Tsuchida K, Matsuda S, Hara R; Cyclopropaneamine compound. Patent WO 2013/022047 A1, Takeda Pharmaceutical Company Ltd., 2013.
101. Kruger RG. Novel Anti-Tumor Activity of Targeted LSD1 Inhibition [Abstract], in Proceedings of the 105th Annual Meeting of the American Association for Cancer Research, AACR, San Diego, CA; 2014 April 5-9.
102. Yang M, Culhane JC, Szewczuk LM, Jalili P, Ball HL, Machius M, Cole PA, Yu H. Structural basis for the inhibition of the LSD1 histone demethylase by the antidepressant trans-2-phenylcyclopropylamine. Biochemistry 2007;46:8058-8065.
103. Binda C, Valente S, Romanenghi M, Pilotto S, Cirilli R, Karytinos A, Ciossani G, Botrugno OA, Forneris F, Tardugno M, Edmondson DE, Minucci S, Mattevi A, Mai A. Biochemical, structural, and biological evaluation of tranylcypromine derivatives as inhibitors of histone demethylases LSD1 and LSD2. J Am Chem Soc 2010;132:6827-6833.
104. Mimasu S, Umezawa N, Sato S, Higuchi T, Umehara T, Yokoyama S. Structurally designed trans-2-phenylcyclopropylamine derivatives potently inhibit histone demethylase LSD1/KDM1. Biochemistry 2010;49:6494-6503.
105. Huang Y, Greene E, Murray Stewart T, Goodwin AC, Baylin SB, Woster PM, Casero RA. Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes. Proc Natl Acad Sci USA 2007;104:8023-8028.
106. Gerner EW, Meyskens FL. Polyamines and cancer: Old molecules, new understanding. Nat Rev Cancer 2004;4:781-792.
107. Zhu Q, Huang Y, Marton L, Woster P, Davidson N, Casero R, Jr. Polyamine analogs modulate gene expression by inhibiting lysine-specific demethylase 1 (LSD1) and altering chromatin structure in human breast cancer cells. Amino Acids 2012;42:887-898.
108. Wang J, Lu F, Ren Q, Sun H, Xu Z, Lan R, Liu Y, Ward D, Quan J, Ye T, Zhang H. Novel histone demethylase LSD1 inhibitors selectively target cancer cells with pluripotent stem cell properties. Cancer Res 2011;71:7238-7249.
109. Willmann D, Lim S, Wetzel S, Metzger E, Jandausch A, Wilk W, Jung M, Forne I, Imhof A, Janzer A, Kirfel J, Waldmann H, Schüle R, Buettner R. Impairment of prostate cancer cell growth by a selective and reversible lysine-specific demethylase 1 inhibitor. Int J Cancer 2012;131:2704-2709.
110. Strauss MJ. The nitroaromatic group in drug design. Pharmacology and toxicology (for nonpharmacologists). Ind Eng Chem Prod Res Dev 1979;18:158-166.
111. Magdy I. A. AAE, Alnamer YA, Gabr YA. Synthesis and chemical reactivity of 2-methylchromones. ARKIVOC 2010;2010:98-135.
112. Hazeldine S, Pachaiyappan B, Steinbergs N, Nowotarski S, Hanson AS, Casero RA, Woster PM. Low molecular weight amidoximes that act as potent inhibitors of lysine-specific demethylase 1. J Med Chem 2012;55:7378-7391.
113. Yu V, Fisch T, Long AM, Tang J, Lee JH, Hierl M, Chen H, Yakowec P, Schwandner R, Emkey R. High-throughput TR-FRET assays for identifying inhibitors of LSD1 and JMJD2C histone lysine demethylases. J Biomol Screen 2012;17:27-38.
114. It is noteworthy that other workers in this area (e.g., see references 117 and 120) have confirmed that CoREST is not required in order to demonstrate activity in the biochemical assay, casting some doubt on this hypothesis. Data kindly provided by Alex Stowell, CRUK Manchester Institute, UK (personal communication) and Emily Thiesen, University of Utah, USA (personal communication).
115. Dulla B, Kirla KT, Rathore V, Deora GS, Kavela S, Maddika S, Chatti K, Reiser O, Iqbal J, Pal M. Synthesis and evaluation of 3-amino/guanidine substituted phenyl oxazoles as a novel class of LSD1 inhibitors with anti-proliferative properties. Org Biomol Chem 2013;11:3103-3107.
116. Dhanak D. Drugging the Cancer Epigenome [Abstract], in Proceedings of the 104th Annual Meeting of the American Association for Cancer Research, AACR, Washington, DC, Philadelphia, PA; 2013 April 6-10.
117. Hitchin, JR, Blagg, J, Burke, R, Burns, S, Cockerill, MJ, Fairweather, EE, Hutton, C, Jordan, AM, McAndrew, C, Mirza, A, Mould, D, Thomson, GT, Waddell, I, Ogilvie, DJ. Development and evaluation of selective, reversible LSD1 inhibitors derived from fragments. Med Chem Comm 2014;4:1513-1522.
118. Heerding DA, Rouse MB, Seefeld MA. Inhibitors of AKT activity. Patent WO 2006/113837 A2, Smithkline Beecham Corp., 2006.
119. Subramanian R, Lee MR, Allen JG, Bourbeau MP, Fotsch C, Hong F-T, Tadesse S, Yao G, Yuan CC, Surapaneni S, Skiles GL, Wang X, Wohlhieter GE, Zeng Q, Zhou Y, Zhu X, Li C. Cytochrome P450-mediated epoxidation of 2-aminothiazole-based AKT inhibitors: Identification of novel GSH adducts and reduction of metabolic activation through structural changes guided by in silico and in vitro screening. Chem Res Toxicol 2010;23:653-663.
120. Sorna V, Theisen ER, Stephens B, Warner SL, Bearss DJ, Vankayalapati H, Sharma S. High-throughput virtual screening identifies novel N′-(1-phenylethylidene)-benzohydrazides as potent, specific, and reversible LSD1 inhibitors. J Med Chem 2013;58:9496-9508.
121. Baell JB, Holloway GA. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J Med Chem 2010;53:2719-2740.
122. Ifa DR, Rodrigues CR, de Alencastro RB, Fraga CAM, Barreiro EJ. A possible molecular mechanism for the inhibition of cysteine proteases by salicylaldehyde N-acylhydrazones and related compounds. Comp Ther Chem 2000;505:11-17.
123. Auld DS, Southall NT, Jadhav A, Johnson RL, Diller DJ, Simeonov A, Austin CP, Inglese J. Characterization of chemical libraries for luciferase inhibitory activity. J Med Chem 2008;51:2372-2386.
124. Ledesma GN, Gonzalez Sierra M, Escandar GM. Spectroscopic and theoretical study of aromatic α-hydroxy hydrazones and their copper(II) complexes in dioxane-water mixtures. Polyhedron 1998;17:1517-1523.
125. Fiskus W, Sharma S, Shah B, Portier BP, Devaraj SGT, Liu K, Iyer SP, Bearss D, Bhalla KN. Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells. Leukemia 2014.
126. Lynch JT. personal communication.
127. Zheng Y-C, Duan Y-C, Ma J-L, Xu R-M, Zi X, Lv W-L, Wang M-M, Ye X-W, Zhu S, Mobley D, Zhu Y-Y, Wang J-W, Li J-F, Wang Z-R, Zhao W, Liu H-M. Triazole-dithiocarbamate based selective lysine specific demethylase 1 (LSD1) inactivators inhibit gastric cancer cell growth, invasion, and migration. J Med Chem 2013;56:8543-8560.
128. Duan Y-C, Ma Y-C, Zhang E, Shi X-J, Wang M-M, Ye X-W, Liu H-M. Design and synthesis of novel 1, 2, 3-triazole-dithiocarbamate hybrids as potential anticancer agents. Eur J Med Chem 2013;62:11-19.
129. Nobel CSI, Kimland M, Lind B, Orrenius S, Slater AFG. Dithiocarbamates induce apoptosis in thymocytes by raising the intracellular level of redox-active copper. J Biol Chem 1995;270:26202-26208.
130. Ye X-W, Zheng Y-C, Duan Y-C, Wang M-M, Yu B, Ren J-L, Ma J-L, Zhang E, Liu H-M. Synthesis and biological evaluation of coumarin-1, 2, 3-triazole-dithiocarbamate hybrids as potent LSD1 inhibitors. MedChemComm 2014;5:650-654.
131. Gnerre C, Catto M, Leonetti F, Weber P, Carrupt P-A, Altomare C, Carotti A, Testa B. Inhibition of monoamine oxidases by functionalized coumarin derivatives: Biological activities, QSARs, and 3D-QSARs. J Med Chem 2000;43:4747-4758.
132. Schmitt ML, Ladwein KI, Carlino L, Schulz-Fincke J, Willmann D, Metzger E, Schilcher P, Imhof A, Schüle R, Sippl W, Jung M. Heterogeneous antibody-based activity assay for lysine specific demethylase 1 (LSD1) on a histone peptide substrate. J Biomol Screen 2014;19:973-978.
133. Plant M, Dineen T, Cheng A, Long AM, Chen H, Morgenstern KA. Screening for lysine-specific demethylase-1 inhibitors using a label-free high-throughput mass spectrometry assay. Anal Biochem 2011;419:217-227.
134. Culhane JC, Szewczuk LM, Liu X, Da G, Marmorstein R, Cole PA. A mechanism-based inactivator for histone demethylase LSD1. J Am Chem Soc 2006;128:4536-4537.
135. Kumarasinghe IR, Woster PM. Synthesis and evaluation of novel cyclic peptide inhibitors of lysine-specific demethylase 1. ACS Med Chem Lett 2013;5:29-33.
136. Tortorici M, Borrello MT, Tardugno M, Chiarelli LR, Pilotto S, Ciossani G, Vellore NA, Bailey SG, Cowan J, O'Connell M, Crabb SJ, Packham G, Mai A, Baron R, Ganesan A, Mattevi A. Protein recognition by short peptide reversible inhibitors of the chromatin-modifying LSD1/CoREST lysine demethylase. ACS Chem Biol 2013;8:1677-1682.