Review

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012, Jinan, Shandong, PR China

Search for more papers by this author

Takayoshi Suzuki^‡

*Author for correspondence:

E-mail Address: suzukit@koto.kpu-m.ac.jp

Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto 606-0823, Japan

CREST, Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan

^‡Authors contributed equally

Search for more papers by this author

Xinyong Liu^‡

**Author for correspondence:

E-mail Address: xinyongllab@163.com

^‡Authors contributed equally

Search for more papers by this author

Peng Zhan^‡

***Author for correspondence:

E-mail Address: zhanpeng1982@sdu.edu.cn

^‡Authors contributed equally

Search for more papers by this author

Published Online:8 Dec 2015https://doi.org/10.2217/epi.15.86

View article

Abstract

LSD1 is an epigenetic modulator associated with transcriptional regulation of genes involved in a broad spectrum of key cellular processes, and its activity is often altered under pathological conditions. LSD1 inhibitors are considered to be candidates for therapy of cancer, viral diseases and neurodegeneration. Many LSD1 inhibitors with various scaffolds have been disclosed, and a few potent molecules are in different stages of clinical development. In this review, we summarize recent biological findings on the roles of LSD1 and the current understanding of the clinical significance of LSD1, and focus on the medicinal chemistry strategies used in the design and development of LSD1 inhibitors as drug-like epigenetic modulators since 2012, including a brief consideration of structure–activity relationships.

Keywords:

Papers of special note have been highlighted as: •• of considerable interest

References

1 Helin K, Dhanak D. Chromatin proteins and modifications as drug targets. Nature 502(7472), 480–488 (2013).
Medline CASGoogle Scholar
2 Fan J, Krautkramer KA, Feldman JL et al. Metabolic regulation of histone post-translational modifications. ACS Chem. Biol. 10(1), 95–108 (2015).
Medline CASGoogle Scholar
3 Suzuki T, Miyata N. Lysine demethylases inhibitors. J. Med. Chem. 54(24), 8236–8250 (2011). •• Introduction to the enzymology of the lysine demethylases, emerging small molecule inhibitors, discuss the potential and challenges of therapeutically targeting them.
Medline CASGoogle Scholar
4 Thinnes CC, England KS, Kawamura A et al. Targeting histone lysine demethylases – progress, challenges, and the future. Biochim. Biophys. Acta 1839(12), 1416–1432 (2014).
Medline CASGoogle Scholar
5 Zheng YC, Ma J, Wang Z et al. A systematic review of histone lysine-specific demethylase 1 and its inhibitors. Med. Res. Rev. doi: 10.1002/med.21350 (2015) (Epub ahead of print).
MedlineGoogle Scholar
6 McGrath J, Trojer P. Targeting histone lysine methylation in cancer. Pharmacol. Ther. 150, 1–22 (2015).
Medline CASGoogle Scholar
7 Højfeldt JW, Agger K, Helin K. Histone lysine demethylases as targets for anticancer therapy. Nat. Rev. Drug Discov. 12(12), 917–930 (2013). •• Demonstrates the roles of members of the histone lysine demethylases in the development of cancers and highlights the therapeutic possibilities and challenges associated with targeting.
Medline CASGoogle Scholar
8 Mould DP, McGonagle AE, Wiseman DH et al. Reversible inhibitors of LSD1 as therapeutic agents in acute myeloid leukemia: clinical significance and progress to date. Med. Res. Rev. 35(3), 586–618 (2015).
Medline CASGoogle Scholar
9 Varier RA, Timmers HT. Histone lysine methylation and demethylation pathways in cancer. Biochim. Biophys. Acta 1815(1), 75–89 (2011).
Medline CASGoogle Scholar
10 Hayami S, Kelly JD, Cho HS et al. Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers. Int. J. Cancer. 128(3), 574–586 (2011).
Medline CASGoogle Scholar
11 Amente S, Lania L, Majello B. The histone LSD1 demethylase in stemness and cancer transcription programs. Biochim. Biophys. Acta 1829(10), 981–986 (2013).
Medline CASGoogle Scholar
12 Chen C, Ge J, Lu Q et al. Expression of Lysine-specific demethylase 1 in human epithelial ovarian cancer. J. Ovarian. Res. 8(1), 28 (2015).
MedlineGoogle Scholar
13 Chen L, Xu Y, Xu B et al. Over-expression of lysine-specific demethylase 1 predicts tumor progression and poor prognosis in human esophageal cancer. Int. J. Clin. Exp. Pathol. 7(12), 8929–8934 (2014).
MedlineGoogle Scholar
14 Niebel D, Kirfel J, Janzen V et al. Lysine-specific demethylase 1 (LSD1) in hematopoietic and lymphoid neoplasms. Blood 124(1), 151–152 (2014).
Medline CASGoogle Scholar
15 Lv T, Yuan D, Miao X et al. Over-expression of LSD1 promotes proliferation, migration and invasion in non-small cell lung cancer. PLoS ONE 7(4), e35065 (2012).
Medline CASGoogle Scholar
16 Hoshino I, Akutsu Y, Murakami K et al. Histone demethylase LSD1 inhibitors prevent cell growth by regulating gene expression in esophageal squamous cell carcinoma cells. Ann. Surg. Oncol. (2015) (Epub ahead of print).
MedlineGoogle Scholar
17 Crea F, Sun L, Mai A et al. The emerging role of histone lysine demethylases in prostate cancer. Mol. Cancer. 11, 52 (2012).
Medline CASGoogle Scholar
18 Sakamoto A, Hino S, Nagaoka K et al. Lysine demethylase LSD1 coordinates glycolytic and mitochondrial metabolism in hepatocellular carcinoma cells. Cancer Res. 75(7), 1445–1456 (2015).
Medline CASGoogle Scholar
19 Hino S, Sakamoto A, Nagaoka K et al. FAD-dependent lysine-specific demethylase-1 regulates cellular energy expenditure. Nat. Commun. 3, 758 (2012).
MedlineGoogle Scholar
20 Zhang F, Xu D, Yuan L et al. Epigenetic regulation of Atrophin1 by lysine-specific demethylase 1 is required for cortical progenitor maintenance. Nat. Commun. 5, 5815 (2012).
Google Scholar
21 Whyte WA, Bilodeau S, Orlando DA et al. Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature 482, 221–225 (2012).
Medline CASGoogle Scholar
22 Duteil D, Metzger E, Willmann D et al. LSD1 promotes oxidative metabolism of white adipose tissue. Nat. Commun. 5, 4093 (2014).
Medline CASGoogle Scholar
23 Abdulla A, Zhang Y, Hsu FN et al. Regulation of lipogenic gene expression by lysine-specific histone demethylase-1 (LSD1). J. Biol. Chem. 289, 29937–29947 (2014).
Medline CASGoogle Scholar
24 Pan D, Mao C, Wang YX. Suppression of gluconeogenic gene expression by LSD1-mediated histone demethylation. PLoS ONE 8, e66294 (2013).
Medline CASGoogle Scholar
25 Cai C, He HH, Gao S et al. Lysine-specific demethylase 1 has dual functions as a major regulator of androgen receptor transcriptional activity. Cell Rep. 9(5), 1618–1627 (2014).
Medline CASGoogle Scholar
26 Wu CY, Hsieh CY, Huang KE et al. Cryptotanshinone down-regulates androgen receptor signaling by modulating lysine-specific demethylase 1 function. Int. J. Cancer 131(6), 1423–1434 (2012).
Medline CASGoogle Scholar
27 Bennani-Baiti IM. Integration of ERα-PELP1-HER2 signaling by LSD1 (KDM1A/AOF2) offers combinatorial therapeutic opportunities to circumventing hormone resistance in breast cancer. Breast Cancer Res. 14, 112 (2012).
Medline CASGoogle Scholar
28 Cortez V, Mann M, Tekmal S et al. Targeting the PELP1-KDM1 axis as a potential therapeutic strategy for breast cancer. Breast Cancer Res. 14(4), R108 (2012).
Medline CASGoogle Scholar
29 Pollock JA, Larrea MD, Jasper JS et al. Lysine-specific histone demethylase 1 inhibitors control breast cancer proliferation in ERα-dependent and -independent manners. ACS Chem. Biol. 7(7), 1221–1231 (2012).
Medline CASGoogle Scholar
30 Laurent B, Ruitu L, Murn J et al. A specific LSD1/KDM1A isoform regulates neuronal differentiation through H3K9 demethylation. Mol. Cell. 57(6), 957–970 (2015).
Medline CASGoogle Scholar
31 Shin J, Ming GL, Song H. Molecular toggle switch of histone demethylase LSD1. Mol. Cell. 57(6), 949–950 (2015).
Medline CASGoogle Scholar
32 Han X, Gui B, Xiong C et al. Destabilizing LSD1 by Jade-2 promotes neurogenesis: an antibraking system in neural development. Mol. Cell. 55(3), 482–494 (2014).
Medline CASGoogle Scholar
33 Li A, He Y, Sun S et al. Lysine-specific demethylase 1 inhibitors protect cochlear spiral ganglion neurons against cisplatin-induced damage. Neuroreport 26(9), 539–547 (2015).
MedlineGoogle Scholar
34 Liang Y, Quenelle D, Vogel JL et al. A novel selective LSD1/KDM1A inhibitor epigenetically blocks herpes simplex virus lytic replication and reactivation from latency. mBio 4(1), e00558–e005512 (2013).
Medline CASGoogle Scholar
35 Bag P, Ojha D, Mukherjee H et al. A dihydro-pyrido-indole potently inhibits HSV-1 infection by interfering the viral immediate early transcriptional events. Antiviral Res. 105, 126–134 (2014).
Medline CASGoogle Scholar
36 Robertson JC, Hurley NC, Tortorici M et al. 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. 9(7), e1003158 (2013).
Medline CASGoogle Scholar
37 Luka Z, Moss F, Loukachevitch LV et al. Histone demethylase LSD1 is a folate-binding protein. Biochemistry 50(21), 4750–4756 (2011).
Medline CASGoogle Scholar
38 Luka Z, Pakhomova S, Loukachevitch LV et al. Crystal structure of the histone lysine specific demethylase LSD1 complexed with tetrahydrofolate. Protein Sci. 23(7), 993–998 (2014).
Medline CASGoogle Scholar
39 Khan MN, Suzuki T, Miyata N. An overview of phenylcyclopropylamine derivatives: biochemical and biological significance and recent developments. Med. Res. Rev. 33(4), 873–910 (2013).
Medline CASGoogle Scholar
40 Vianello P, Botrugno OA, Cappa A et al. Synthesis, biological activity and mechanistic insights of 1-substituted cyclopropylamine derivatives: a novel class of irreversible inhibitors of histone demethylase KDM1A. Eur. J. Med. Chem. 86, 352–363 (2014).
Medline CASGoogle Scholar
41 Pieroni M, Annunziato G, Azzali E et al. Further insights into the SAR of α-substituted cyclopropylamine derivatives as inhibitors of histone demethylase KDM1A. Eur. J. Med. Chem. 92, 377–386 (2015).
Medline CASGoogle Scholar
42 Valente S, Rodriguez V, Mercurio C et al. Pure enantiomers of benzoylamino-tranylcypromine: LSD1 inhibition, gene modulation in human leukemia cells and effects on clonogenic potential of murine promyelocytic blasts. Eur. J. Med. Chem. 94, 163–174 (2015).
Medline CASGoogle Scholar
43 Valente S, Rodriguez V, Mercurio C et al. Pure diastereomers of a tranylcypromine-based LSD1 inhibitor: enzyme selectivity and in-cell studies. ACS Med. Chem. Lett. 6(2), 173–177 (2014).
MedlineGoogle Scholar
44 Mohammad H, Smitheman K, Cusan M et al. Inhibition of LSD1 as a therapeutic strategy for the treatment of acute myeloid leukemia. Blood 122(21), 3964 (2013).
MedlineGoogle Scholar
45 Kruger RG. Novel anti-tumor activity of targeted LSD1 inhibition. Presented at: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research. San Diego, CA, USA, 5–9 April (2014).
Google Scholar
46 Neelamegam R, Ricq EL, Malvaez M et al. Brain-penetrant LSD1 inhibitors can block memory consolidation. ACS Chem. Neurosci. 3(2), 120–128 (2012).
Medline CASGoogle Scholar
47 Rivers A, Vaitkus K, Ruiz MA et al. RN-1, a potent and selective LSD1 inhibitor, increases γ-globin expression, f-retics, and f-cells in a sickle cell disease mouse model. Exp. Hematol. 43(7), 546–553 (2015).
Medline CASGoogle Scholar
48 Fang Z, Song Y, Zhan P et al. Conformational restriction: an effective tactic in ‘follow-on’-based drug discovery. Future Med. Chem. 6(8), 885–901 (2014).
Medline CASGoogle Scholar
49 Rodriguez V, Valente S, Rovida S et al. Pyrrole- and indole- containing tranylcypromine derivatives as novel lysine-specific demethylase 1 inhibitors active on cancer cells. Med. Chem. Commun. 6, 665–670 (2014).
Google Scholar
50 Zhan P, Song Y, Itoh Y et al. Recent advances in the structure-based rational design of TNKSIs. Mol. Biosyst. 10(11), 2783–2799 (2014).
Medline CASGoogle Scholar
51 Kang D, Song Y, Chen W et al. 'Old dogs with new tricks': exploiting alternative mechanisms of action and new drug design strategies for clinically validated HIV targets. Mol. Biosyst. 10(8), 1998–2022 (2014).
Medline CASGoogle Scholar
52 Ueda R, Suzuki T, Mino K et al. Identification of cell-active lysine specific demethylase 1-selective inhibitors. J. Am. Chem. Soc. 131(48), 17536–17537 (2009). •• Reports on the identification of the first small-molecule LSD1-selective inhibitors.
Medline CASGoogle Scholar
53 Etani T, Suzuki T, Naiki T et al. NCL1, a highly selective lysine-specific demethylase 1 inhibitor, suppresses prostate cancer without adverse effect. Oncotarget 6(5), 2865–2878 (2015).
MedlineGoogle Scholar
54 Pajtler KW, Weingarten C, Thor T et al. The KDM1A histone demethylase is a promising new target for the epigenetic therapy of medulloblastoma. Acta Neuropathol. Commun. 1(1), 19 (2013).
MedlineGoogle Scholar
55 Guibourt N, Ortega MA, Castro-Palomino LJ: WO2010043721 (2010).
Google Scholar
56 Khan MNA, Tsumoto H, Itoh Y et al. Design, synthesis, and biological activity of N-alkylated analogue of NCL1, a selective inhibitor of lysine-specific demethylase 1. Med. Chem. Commun. 6, 407–412 (2015).
Google Scholar
57 Kumarasinghe IR, Woster PM. Synthesis and evaluation of novel cyclic peptide inhibitors of lysine-specific demethylase 1. ACS Med. Chem. Lett. 5(1), 29–33 (2013).
MedlineGoogle Scholar
58 Tortorici M, Borrello MT, Tardugno M et al. Protein recognition by short peptide reversible inhibitors of the chromatin-modifying LSD1/CoREST lysine demethylase. ACS Chem. Biol. 8(8), 1677–82 (2013).
Medline CASGoogle Scholar
59 Kakizawa T, Ota Y, Itoh Y et al. Histone H3 peptide based LSD1-selective inhibitors. Bioorg. Med. Chem. Lett. 25(9), 1925–1928 (2015).
Medline CASGoogle Scholar
60 Ogasawara D, Itoh Y, Tsumoto H et al. Lysine-specific demethylase 1-selective inactivators: protein-targeted drug delivery mechanism. Angew. Chem. Int. Ed. Engl. 52(33), 8620–8624 (2013).
Medline CASGoogle Scholar
61 Itoh Y, Ogasawara D, Ota Y et al. Synthesis, LSD1 inhibitory activity, and LSD1 binding model of optically pure lysine-PCPA conjugates. Comput. Struct. Biotechnol. J. 9, e201402002 (2014).
MedlineGoogle Scholar
62 Zhan P, Liu X. Rationally designed multitarget anti-HIV agents. Curr. Med. Chem. 20(13), 1743–58 (2013).
Medline CASGoogle Scholar
63 Zhan P, Liu X. Designed multiple ligands: an emerging anti-HIV drug discovery paradigm. Curr. Pharm. Des. 15(16), 1893–917 (2009).
Medline CASGoogle Scholar
64 Han H, Yang X, Pandiyan K et al. Synergistic re-activation of epigenetically silenced genes by combinatorial inhibition of DNMTs and LSD1 in cancer cells. PLoS ONE 8(9), e75136 (2013).
Medline CASGoogle Scholar
65 Huang Y, Stewart TM, Wu Y et al. Novel oligoamine analogues inhibit lysine-specific demethylase 1 and induce reexpression of epigenetically silenced genes. Clin. Cancer Res. 15, 7217–7228 (2009).
Medline CASGoogle Scholar
66 Vasilatos SN, Katz TA, Oesterreich S et al. Crosstalk between lysine-specific demethylase 1 (LSD1) and histone deacetylases mediates antineoplastic efficacy of HDAC inhibitors in human breast cancer cells. Carcinogenesis 34(6), 1196–1207 (2013).
Medline CASGoogle Scholar
67 Singh MM, Johnson B, Venkatarayan A et al. Preclinical activity of combined HDAC and KDM1A inhibition in glioblastoma. Neuro Oncol. 17(11), 1463–1473 (2015).
Medline CASGoogle Scholar
68 Wissmann M, Yin N, Müller JM et al. Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression. Nat. Cell Biol. 9(3), 347–353 (2007).
Medline CASGoogle Scholar
69 Song Y, Xu H, Chen W et al. 8-Hydroxyquinoline: a privileged structure with broad-ranging pharmacological potentials. Med. Chem. Commun. 6, 61–74 (2015).
CASGoogle Scholar
70 Rotili D, Tomassi S, Conte M et al. Pan-histone demethylase inhibitors simultaneously targeting Jumonji C and lysine-specific demethylases display high anticancer activities. J. Med. Chem. 57, 42–55 (2014).
Medline CASGoogle Scholar
71 Schmitt ML, Hauser AT, Carlino L et al. Nonpeptidic propargylamines as inhibitors of lysine specific demethylase 1 (LSD1) with cellular activity. J. Med. Chem. 56(18), 7334–7342 (2013).
Medline CASGoogle Scholar
72 Wang J, Lu F, Ren Q et al. Novel histone demethylase LSD1 inhibitors selectively target cancer cells with pluripotent stem cell properties. Cancer Res. 71(23), 7238–7249 (2011).
Medline CASGoogle Scholar
73 Hsu HC, Liu YS, Tseng KC et al. CBB1003, a lysine-specific demethylase 1 inhibitor, suppresses colorectal cancer cells growth through down-regulation of leucine-rich repeat-containing G-protein-coupled receptor 5 expression. J. Cancer Res. Clin. Oncol. 141(1), 11–21 (2015).
Medline CASGoogle Scholar
74 Prusevich P, Kalin JH, Ming SA et al. A selective phenelzine analogue inhibitor of histone demethylase LSD1. ACS Chem. Biol. 9(6), 1284–1293 (2014).
Medline CASGoogle Scholar
75 Sorna V, Theisen ER, Stephens B et al. High-throughput virtual screening identifies novel N’;-(1-phenylethylidene)-benzohydrazides as potent, specific, and reversible LSD1 inhibitors. J. Med. Chem. 56(23), 9496–9508 (2013). •• The first reversible and specific LSD1 inhibitor was identified by high-throughput virtual screening.
Medline CASGoogle Scholar
76 Theisen ER, Gajiwala S, Bearss J et al. Reversible inhibition of lysine specific demethylase 1 is a novel anti-tumor strategy for poorly differentiated endometrial carcinoma. BMC Cancer 14, 752 (2014).
MedlineGoogle Scholar
77 Fiskus W, Sharma S, Shah B et al. Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells. Leukemia 28(11), 2155–2164 (2014).
Medline CASGoogle Scholar
78 Zhou Y, Li Y, Wang W et al. Synthesis and biological evaluation of novel (E)-N’-(2, 3-dihydro-1H-inden-1-ylidene) benzohydrazides as potent LSD1 inhibitors. Bioorg. Med. Chem. Lett. doi: 10.1016/j.bmcl.2015.06.054 (2015).
Google Scholar
79 Hazeldine S, Pachaiyappan B, Steinbergs N et al. Low molecular weight amidoximes that act as potent inhibitors of lysine-specific demethylase 1. J. Med. Chem. 55(17), 7378–7391 (2012).
Medline CASGoogle Scholar
80 Zheng YC, Duan YC, Ma JL et al. Triazole-dithiocarbamate based selective lysine specific demethylase 1 (LSD1) inactivators inhibit gastric cancer cell growth, invasion, and migration. J. Med. Chem. 56(21), 8543–8560 (2013).
Medline CASGoogle Scholar
81 Ye XW, Zheng YC, Duan YC et al. Synthesis and biological evaluation of coumarin-1, 2, 3-triazole-dithiocarbamate hybrids as potent LSD1 inhibitors. Med. Chem. Commun. 5, 650–654 (2014).
CASGoogle Scholar
82 Ma LY, Zheng YC, Wang SQ et al. Design, synthesis, and structure-activity relationship of novel LSD1 inhibitors based on pyrimidine-thiourea hybrids as potent, orally active antitumor agents. J. Med. Chem. 58(4), 1705–1716 (2015).
Medline CASGoogle Scholar
83 Dulla B, Kirla KT, Rathore V et al. Synthesis and evaluation of 3-amino/guanidine substituted phenyl oxazoles as a novel class of LSD1 inhibitors with anti-proliferative properties. Org. Biomol. Chem. 11(19), 3103–3107 (2013).
Medline CASGoogle Scholar
84 Kutz CJ, Holshouser SL, Marrow EA et al. 3,5-Diamino-1,2,4-triazoles as a novel scaffold for potent, reversible LSD1 (KDM1A) inhibitors. Med. Chem. Commun. 5(12), 1863–1870 (2014).
CASGoogle Scholar
85 Kutz CJ, Holshouser SL, Woster PM. Small molecule epigenetic modulators for the treatment of cardiovascular disorders. Presented at: Abstracts of Papers, 249th ACS National Meeting and Exposition. CO, USA, 22–26 March (2015).
Google Scholar
86 Newman DJ, Cragg GM. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J. Nat. Prod. 75(3), 311–335 (2012).
Medline CASGoogle Scholar
87 Newman DJ, Cragg GM. Natural products as sources of new drugs over the last 25 years. J. Nat. Prod. 70(3), 461–477 (2007).
Medline CASGoogle Scholar
88 Newman DJ, Cragg GM, Snader KM. Natural products as sources of new drugs over the period 1981–2002. J. Nat. Prod. 66(7), 1022–1037 (2003).
Medline CASGoogle Scholar
89 Abdulla A, Zhao X, Yang F. Natural polyphenols inhibit lysine-specific demethylase-1 in vitro. J. Biochem. Pharmacol. Res. 1(1), 56–63 (2013).
Medline CASGoogle Scholar
90 Huang Y, Greene E, Murray Stewart T et al. Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes. Proc. Natl Acad. Sci. USA 104, 8023–8028 (2007).
Medline CASGoogle Scholar
91 Zhu Q, Huang Y, Marton LJ et al. Polyamine analogs modulate gene expression by inhibiting lysine-specific demethylase 1 (LSD1) and altering chromatin structure in human breast cancer cells. Amino Acids 42, 887–898 (2012).
Medline CASGoogle Scholar
92 Murray-Stewart T, Woster PM, Casero RA Jr. The re-expression of the epigenetically silenced e-cadherin gene by a polyamine analogue lysine-specific demethylase-1 (LSD1) inhibitor in human acute myeloid leukemia cell lines. Amino Acids 46, 585–594 (2014).
Medline CASGoogle Scholar
93 Müller G. Medicinal chemistry of target family-directed masterkeys. Drug Discov. Today. 8(15), 681–691 (2003).
Medline CASGoogle Scholar
94 Song Y, Chen W, Kang D et al. 'Old friends in new guise': exploiting privileged structures for scaffold re-evolution/refining. Comb. Chem. High Throughput Screen. 17(6), 536–553 (2014).
Medline CASGoogle Scholar
95 Bauer RA. Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies. Drug Discov. Today 20(9), 1061–1073 (2015).
Medline CASGoogle Scholar
96 Kim SA, Chatterjee N, Jennings MJ et al. Extranucleosomal DNA enhances the activity of the LSD1/CoREST histone demethylase complex. Nucleic Acids Res. 43(10), 4868–4880 (2015).
Medline CASGoogle Scholar
97 Zhan P, Itoh Y, Suzuki T et al. Strategies for the discovery of target-specific or isoform-selective modulators. J. Med. Chem. doi:10.10-763321/acs.jmedchem.5b00229 (2015). •• Discusses currently available rational design strategies for obtaining class- and isoform-selective inhibitors.
Google Scholar
98 Lolli M, Narramore S, Fishwick CW et al. Refining the chemical toolbox to be fit for educational and practical purpose for drug discovery in the 21st Century. Drug Discov. Today doi: 10.1016/j.drudis.2015.04.010 (2015).
MedlineGoogle Scholar
99 Zhao F, Liu N, Zhan P et al. Repurposing of HDAC inhibitors towards anti-HCV drug discovery: how to teach old dog new tricks? Future Med. Chem. 7(11), 1367–1371 (2015).
Medline CASGoogle Scholar

Vol. 7, No. 8

Metrics

Downloaded 442 times

History

Published online 8 December 2015

Published in print December 2015

Information

Keywords

Financial & competing interests disclosure

The authors gratefully acknowledge financial support from the National Natural Science Foundation of China (no. 81573347), the Science and Technology Development Project of Shandong Province (no. 2014GSF118012), Postdoctoral Fellow Allowance (ID no. P12418) from Japan Society for the Promotion of Science (JSPS), JST CREST program, Takeda Science Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Scientific Research from JSPS, the Tokyo Biochemical Research Foundation (T Suzuki), and the Uehara Memorial Foundation (T Suzuki). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

PDF download

Medicinal chemistry insights in the discovery of novel LSD1 inhibitors

Abstract

References