Structure-based design and discovery of potent and selective lysine-specific demethylase 1 (LSD1) inhibitors
[Display omitted] •A series of highly potent and selective reversible LSD1 inhibitors were discovered employing structure-based drug design.•Potent induction of cellular differentiation marker CD11b in THP-1 was demonstrated with reversible LSD1 inhibitors.•Optimization of indazole analogs led to co...
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Published in | Bioorganic & medicinal chemistry letters Vol. 29; no. 1; pp. 103 - 106 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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01.01.2019
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Abstract | [Display omitted]
•A series of highly potent and selective reversible LSD1 inhibitors were discovered employing structure-based drug design.•Potent induction of cellular differentiation marker CD11b in THP-1 was demonstrated with reversible LSD1 inhibitors.•Optimization of indazole analogs led to compounds with desirable potency, hERG inhibition profile, and oral PK properties.
The histone demethylase LSD1 is a key enzyme in the epigenetic regulation of gene transcription. Here we present our efforts to discover small molecule reversible inhibitors of LSD1 as an attractive approach to treat hematologic malignancies and certain solid tumors. Using structure-based drug design, we designed and synthesized a novel series of heteroaromatic imidazole inhibitors that demonstrate potent inhibition of the demethylase activity and low nanomolar cell-based activity. This novel LSD1 inhibitor series was further optimized by attenuating the hERG inhibition and improving oral bioavailability. |
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AbstractList | The histone demethylase LSD1 is a key enzyme in the epigenetic regulation of gene transcription. Here we present our efforts to discover small molecule reversible inhibitors of LSD1 as an attractive approach to treat hematologic malignancies and certain solid tumors. Using structure-based drug design, we designed and synthesized a novel series of heteroaromatic imidazole inhibitors that demonstrate potent inhibition of the demethylase activity and low nanomolar cell-based activity. This novel LSD1 inhibitor series was further optimized by attenuating the hERG inhibition and improving oral bioavailability. [Display omitted] •A series of highly potent and selective reversible LSD1 inhibitors were discovered employing structure-based drug design.•Potent induction of cellular differentiation marker CD11b in THP-1 was demonstrated with reversible LSD1 inhibitors.•Optimization of indazole analogs led to compounds with desirable potency, hERG inhibition profile, and oral PK properties. The histone demethylase LSD1 is a key enzyme in the epigenetic regulation of gene transcription. Here we present our efforts to discover small molecule reversible inhibitors of LSD1 as an attractive approach to treat hematologic malignancies and certain solid tumors. Using structure-based drug design, we designed and synthesized a novel series of heteroaromatic imidazole inhibitors that demonstrate potent inhibition of the demethylase activity and low nanomolar cell-based activity. This novel LSD1 inhibitor series was further optimized by attenuating the hERG inhibition and improving oral bioavailability. |
Author | Del Rosario, Joselyn R. Chen, Young K. Shi, Lihong Lai, Chon Kanouni, Toufike Nie, Zhe Stafford, Jeffrey A. Cho, Robert W. Veal, James M. Stansfield, Ryan K. Severin, Christophe Xu, Jiangchun |
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Cites_doi | 10.1093/carcin/bgp324 10.1016/j.molcel.2012.11.006 10.1016/j.ccr.2012.03.014 10.1158/0008-5472.CAN-06-1570 10.3390/molecules23071538 10.1182/blood-2014-04-569525 10.2217/epi-2017-0022 10.1111/j.1399-0004.2011.01809.x 10.2147/OTT.S145971 10.1158/0008-5472.CAN-08-1735 10.1016/j.bmcl.2017.08.052 10.1021/jm060379l 10.1038/nature12751 10.1038/bjc.2013.364 10.4155/fmc-2017-0068 10.1021/acs.jmedchem.7b00462 10.1002/med.21334 10.1158/0008-5472.CAN-10-2442 10.1016/j.cell.2004.12.012 |
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Keywords | Epigenetics Demethylase Structure-based drug design Lysine-specific demethylase 1 LSD1 LSD1 Structure-based drug design REVERSIBLE INHIBITORS DERIVATIVES |
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References | Niwa, Sato, Hashimoto, Matsuno, Umehara (b0105) 2018; 23 Niebel, Kirfel, Janzen, Höller, Majores, Gütgemann (b0030) 2014; 124 Castelli, Pelosi, Testa (b0035) 2017; 11 Dhanak (b0090) 2013 Lim, Janzer, Becker (b0050) 2010; 31 Black, Van Rechem, Whetstine (b0010) 2012; 48 Rao, Chinnasamy, Hong (b0055) 2011; 71 Jamieson, Moir, Rankovic, Wishart (b0110) 2006; 49 Fu, Zhang, Yu (b0070) 2017; 9 Mould, Bremberg, Jordan (b0080) 2017; 27 Schenk, Chen, Gollner (b0100) 2012; 605 Mould, Alli, Bremberg (b0085) 2017; 60 Harris, Huang, Lynch (b0040) 2012; 21 Thomas, Shikhar Sharma, Hallin (b0095) 2015 Schulte, Lim, Schramm (b0045) 2009; 69 Kah, Gullotti, Heukamp (b0060) 2006; 66 Ding, Zhang, Xia (b0065) 2013; 109 Mould, McGonagle, Wiseman, Williams, Jordan (b0075) 2015; 35 Kanwal, Gupta (b0005) 2012; 81 Chen, Y.; Kanoui, T.; Nie, Z.; Stafford, J.; Veal, J. “Inhibitors of Lysine Specific Demethylase-1”. WO2016/004105. Shi, Lan, Matson (b0020) 2004; 119 Hosseini, Minucci (b0025) 2017; 9 Helin, Dhanak (b0015) 2013; 502 Mould, DP (WOS:000352630400005) 2015; 35 Thomas, A (000453230700021.23) 2015 Mould, DP (WOS:000413131400004) 2017; 60 (000453230700021.1) 1000 Castelli, G (WOS:000419093800001) 2018; 11 Shi, YJ (WOS:000226109700007) 2004; 119 Black, JC (WOS:000311919500004) 2012; 48 Fu, XL (WOS:000406051300009) 2017; 9 Harris, WJ (WOS:000303187400006) 2012; 21 Ding, J (WOS:000323417100023) 2013; 109 Schenk, T (000453230700021.20) 2012; 605 Mould, DP (WOS:000412863700029) 2017; 27 Lim, S (WOS:000275245200026) 2010; 31 Rao, M (WOS:000291637100015) 2011; 71 Dhanak, D. (000453230700021.4) 2013 Niebel, D (WOS:000342618300022) 2014; 124 Helin, K (WOS:000325988400042) 2013; 502 Hosseini, A (WOS:000408645600007) 2017; 9 Kanwal, R (WOS:000301489700001) 2012; 81 Schulte, JH (WOS:000263937800049) 2009; 69 Jamieson, C (WOS:000239818200001) 2006; 49 Kahl, P (WOS:000242614300036) 2006; 66 Niwa, H (WOS:000445301800041) 2018; 23 Dhanak (10.1016/j.bmcl.2018.11.001_b0090) 2013 Niwa (10.1016/j.bmcl.2018.11.001_b0105) 2018; 23 Fu (10.1016/j.bmcl.2018.11.001_b0070) 2017; 9 Hosseini (10.1016/j.bmcl.2018.11.001_b0025) 2017; 9 Niebel (10.1016/j.bmcl.2018.11.001_b0030) 2014; 124 Castelli (10.1016/j.bmcl.2018.11.001_b0035) 2017; 11 10.1016/j.bmcl.2018.11.001_b0115 Schulte (10.1016/j.bmcl.2018.11.001_b0045) 2009; 69 Ding (10.1016/j.bmcl.2018.11.001_b0065) 2013; 109 Kanwal (10.1016/j.bmcl.2018.11.001_b0005) 2012; 81 Mould (10.1016/j.bmcl.2018.11.001_b0080) 2017; 27 Kah (10.1016/j.bmcl.2018.11.001_b0060) 2006; 66 Helin (10.1016/j.bmcl.2018.11.001_b0015) 2013; 502 Mould (10.1016/j.bmcl.2018.11.001_b0075) 2015; 35 Schenk (10.1016/j.bmcl.2018.11.001_b0100) 2012; 605 Thomas (10.1016/j.bmcl.2018.11.001_b0095) 2015 Rao (10.1016/j.bmcl.2018.11.001_b0055) 2011; 71 Jamieson (10.1016/j.bmcl.2018.11.001_b0110) 2006; 49 Lim (10.1016/j.bmcl.2018.11.001_b0050) 2010; 31 Black (10.1016/j.bmcl.2018.11.001_b0010) 2012; 48 Shi (10.1016/j.bmcl.2018.11.001_b0020) 2004; 119 Mould (10.1016/j.bmcl.2018.11.001_b0085) 2017; 60 Harris (10.1016/j.bmcl.2018.11.001_b0040) 2012; 21 |
References_xml | – volume: 60 start-page: 7984 year: 2017 ident: b0085 article-title: Development of (4-Cyanophenyl)glycine derivatives as reversible inhibitors of lysine specific demethylase 1 publication-title: J Med Chem contributor: fullname: Bremberg – volume: 27 start-page: 4755 year: 2017 ident: b0080 article-title: Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1 publication-title: Bioorg Med Chem Lett contributor: fullname: Jordan – volume: 21 start-page: 473 year: 2012 ident: b0040 article-title: The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells publication-title: Cancer Cell contributor: fullname: Lynch – volume: 119 start-page: 941 year: 2004 ident: b0020 article-title: Histone demethylation mediated by the nuclear amine oxidase homolog LSD1 publication-title: ell. contributor: fullname: Matson – volume: 9 start-page: 1227 year: 2017 ident: b0070 article-title: Advances toward LSD1 inhibitors for cancer therapy publication-title: Future Med Chem contributor: fullname: Yu – volume: 23 start-page: 1538 year: 2018 ident: b0105 article-title: Crystal Structure of LSD1 in complex with 4-[5-(Piperidin-4-ylmethoxy)-2-( publication-title: Molecules contributor: fullname: Umehara – year: 2013 ident: b0090 article-title: “Drugging the Cancer Epigenome.” Abstract In Proceedings of the 104th Annual Meeting of the American Association for Cancer Research contributor: fullname: Dhanak – volume: 69 start-page: 2065 year: 2009 ident: b0045 article-title: Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy publication-title: Cancer Res contributor: fullname: Schramm – volume: 66 start-page: 11341 year: 2006 ident: b0060 article-title: Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence publication-title: Cancer Res contributor: fullname: Heukamp – start-page: 18 year: 2015 end-page: 22 ident: b0095 article-title: “Growth inhibition of SCLC cell lines by treatment with LSD1 inhibitors is associated with modulation of neuroendocrine pathways” contributor: fullname: Hallin – volume: 605 year: 2012 ident: b0100 article-title: Inhibition of the LSD1 (KDM1A) demethylase reactivates the all- publication-title: Nat Med contributor: fullname: Gollner – volume: 124 start-page: 151 year: 2014 ident: b0030 article-title: Lysine-specific demethylase 1 (LSD1) in hematopoietic and lymphoid neoplasms publication-title: Blood contributor: fullname: Gütgemann – volume: 502 start-page: 480 year: 2013 ident: b0015 article-title: Chromatin proteins and modifications as drug targets publication-title: Nature contributor: fullname: Dhanak – volume: 9 start-page: 1123 year: 2017 ident: b0025 article-title: A comprehensive review of lysine-specific demethylase 1 and its roles in cancer publication-title: Epigenomics contributor: fullname: Minucci – volume: 71 start-page: 4192 year: 2011 ident: b0055 article-title: Inhibition of histone lysine methylation enhances cancer-testis antigen expression in lung cancer cells: implications for adoptive immunotherapy of cancer publication-title: Cancer Res contributor: fullname: Hong – volume: 81 start-page: 303 year: 2012 ident: b0005 article-title: Epigenetic modifications in cancer publication-title: Clin Genet contributor: fullname: Gupta – volume: 11 start-page: 131 year: 2017 ident: b0035 article-title: Targeting histone methyltransferase and demethylase in acute myeloid leukemia therapy publication-title: Onco Targets Ther contributor: fullname: Testa – volume: 109 start-page: 994 year: 2013 ident: b0065 article-title: LSD1-mediated epigenetic modification contributes to proliferation and metastasis of colon cancer publication-title: Br J Cancer contributor: fullname: Xia – volume: 48 start-page: 491 year: 2012 ident: b0010 article-title: Histone lysine methylation dynamics: establishment, regulation, and biological impact publication-title: Mol Cell contributor: fullname: Whetstine – volume: 49 start-page: 5029 year: 2006 ident: b0110 article-title: Medicinal chemistry of hERG optimizations: highlights and hang-ups publication-title: J Med Chem contributor: fullname: Wishart – volume: 31 start-page: 512 year: 2010 ident: b0050 article-title: Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology publication-title: Carcinogenesis contributor: fullname: Becker – volume: 35 start-page: 586 year: 2015 ident: b0075 article-title: Reversible inhibitors of LSD1 as therapeutic agents in acute myeloid leukemia: clinical significance and progress to date publication-title: Med Res Rev contributor: fullname: Jordan – volume: 31 start-page: 512 year: 2010 ident: WOS:000275245200026 article-title: Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology publication-title: CARCINOGENESIS doi: 10.1093/carcin/bgp324 contributor: fullname: Lim, S – volume: 48 start-page: 491 year: 2012 ident: WOS:000311919500004 article-title: Histone Lysine Methylation Dynamics: Establishment, Regulation, and Biological Impact publication-title: MOLECULAR CELL doi: 10.1016/j.molcel.2012.11.006 contributor: fullname: Black, JC – volume: 21 start-page: 473 year: 2012 ident: WOS:000303187400006 article-title: The Histone Demethylase KDM1A Sustains the Oncogenic Potential of MLL-AF9 Leukemia Stem Cells publication-title: CANCER CELL doi: 10.1016/j.ccr.2012.03.014 contributor: fullname: Harris, WJ – volume: 66 start-page: 11341 year: 2006 ident: WOS:000242614300036 article-title: Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence publication-title: CANCER RESEARCH doi: 10.1158/0008-5472.CAN-06-1570 contributor: fullname: Kahl, P – volume: 119 start-page: 941 year: 2004 ident: WOS:000226109700007 article-title: Histone demethylation mediated by the nuclear arnine oxidase homolog LSD1 publication-title: CELL contributor: fullname: Shi, YJ – volume: 23 start-page: ARTN 1538 year: 2018 ident: WOS:000445301800041 article-title: Crystal Structure of LSD1 in Complex with 4-[5-(Piperidin-4-ylmethoxy)-2-(p-tolyl)pyridin-3-yl]benzonitrile publication-title: MOLECULES doi: 10.3390/molecules23071538 contributor: fullname: Niwa, H – year: 2013 ident: 000453230700021.4 article-title: Drugging the Cancer Epigenome publication-title: 104 ANN M AM ASS CAN contributor: fullname: Dhanak, D. – volume: 124 start-page: 151 year: 2014 ident: WOS:000342618300022 article-title: Lysine-specific demethylase 1 (LSD1) in hematopoietic and lymphoid neoplasms publication-title: BLOOD doi: 10.1182/blood-2014-04-569525 contributor: fullname: Niebel, D – start-page: 18 year: 2015 ident: 000453230700021.23 publication-title: Growth inhibition of SCLC cell lines by treatment with LSD1 inhibitors is associated with modulation of neuroendocrine pathways contributor: fullname: Thomas, A – volume: 9 start-page: 1123 year: 2017 ident: WOS:000408645600007 article-title: A comprehensive review of lysine-specific demethylase 1 and its roles in cancer publication-title: EPIGENOMICS doi: 10.2217/epi-2017-0022 contributor: fullname: Hosseini, A – volume: 81 start-page: 303 year: 2012 ident: WOS:000301489700001 article-title: Epigenetic modifications in cancer publication-title: CLINICAL GENETICS doi: 10.1111/j.1399-0004.2011.01809.x contributor: fullname: Kanwal, R – volume: 11 start-page: 131 year: 2018 ident: WOS:000419093800001 article-title: Targeting histone methyltransferase and demethylase in acute myeloid leukemia therapy publication-title: ONCOTARGETS AND THERAPY doi: 10.2147/OTT.S145971 contributor: fullname: Castelli, G – volume: 605 year: 2012 ident: 000453230700021.20 article-title: Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. publication-title: Nat Med. contributor: fullname: Schenk, T – year: 1000 ident: 000453230700021.1 publication-title: Inhibitors of Lysine Specific Demethylase-1 – volume: 69 start-page: 2065 year: 2009 ident: WOS:000263937800049 article-title: Lysine-Specific Demethylase 1 Is Strongly Expressed in Poorly Differentiated Neuroblastoma: Implications for Therapy publication-title: CANCER RESEARCH doi: 10.1158/0008-5472.CAN-08-1735 contributor: fullname: Schulte, JH – volume: 27 start-page: 4755 year: 2017 ident: WOS:000412863700029 article-title: Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1 publication-title: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS doi: 10.1016/j.bmcl.2017.08.052 contributor: fullname: Mould, DP – volume: 49 start-page: 5029 year: 2006 ident: WOS:000239818200001 article-title: Medicinal chemistry of hERG optimizations: Highlights and hang-ups publication-title: JOURNAL OF MEDICINAL CHEMISTRY doi: 10.1021/jm060379l contributor: fullname: Jamieson, C – volume: 502 start-page: 480 year: 2013 ident: WOS:000325988400042 article-title: Chromatin proteins and modifications as drug targets publication-title: NATURE doi: 10.1038/nature12751 contributor: fullname: Helin, K – volume: 109 start-page: 994 year: 2013 ident: WOS:000323417100023 article-title: LSD1-mediated epigenetic modification contributes to proliferation and metastasis of colon cancer publication-title: BRITISH JOURNAL OF CANCER doi: 10.1038/bjc.2013.364 contributor: fullname: Ding, J – volume: 9 start-page: 1227 year: 2017 ident: WOS:000406051300009 article-title: Advances toward LSD1 inhibitors for cancer therapy publication-title: FUTURE MEDICINAL CHEMISTRY doi: 10.4155/fmc-2017-0068 contributor: fullname: Fu, XL – volume: 60 start-page: 7984 year: 2017 ident: WOS:000413131400004 article-title: Development of (4-Cyanophenyl)glycine Derivatives as Reversible Inhibitors of Lysine Specific Demethylase 1 publication-title: JOURNAL OF MEDICINAL CHEMISTRY doi: 10.1021/acs.jmedchem.7b00462 contributor: fullname: Mould, DP – volume: 35 start-page: 586 year: 2015 ident: WOS:000352630400005 article-title: Reversible Inhibitors of LSD1 as Therapeutic Agents in Acute Myeloid Leukemia: Clinical Significance and Progress to Date publication-title: MEDICINAL RESEARCH REVIEWS doi: 10.1002/med.21334 contributor: fullname: Mould, DP – volume: 71 start-page: 4192 year: 2011 ident: WOS:000291637100015 article-title: Inhibition of Histone Lysine Methylation Enhances Cancer-Testis Antigen Expression in Lung Cancer Cells: Implications for Adoptive Immunotherapy of Cancer publication-title: CANCER RESEARCH doi: 10.1158/0008-5472.CAN-10-2442 contributor: fullname: Rao, M – year: 2013 ident: 10.1016/j.bmcl.2018.11.001_b0090 contributor: fullname: Dhanak – volume: 35 start-page: 586 issue: 3 year: 2015 ident: 10.1016/j.bmcl.2018.11.001_b0075 article-title: Reversible inhibitors of LSD1 as therapeutic agents in acute myeloid leukemia: clinical significance and progress to date publication-title: Med Res Rev doi: 10.1002/med.21334 contributor: fullname: Mould – volume: 27 start-page: 4755 issue: 20 year: 2017 ident: 10.1016/j.bmcl.2018.11.001_b0080 article-title: Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1 publication-title: Bioorg Med Chem Lett doi: 10.1016/j.bmcl.2017.08.052 contributor: fullname: Mould – volume: 21 start-page: 473 issue: 4 year: 2012 ident: 10.1016/j.bmcl.2018.11.001_b0040 article-title: The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells publication-title: Cancer Cell doi: 10.1016/j.ccr.2012.03.014 contributor: fullname: Harris – volume: 69 start-page: 2065 issue: 5 year: 2009 ident: 10.1016/j.bmcl.2018.11.001_b0045 article-title: Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy publication-title: Cancer Res doi: 10.1158/0008-5472.CAN-08-1735 contributor: fullname: Schulte – volume: 66 start-page: 11341 issue: 23 year: 2006 ident: 10.1016/j.bmcl.2018.11.001_b0060 article-title: Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence publication-title: Cancer Res doi: 10.1158/0008-5472.CAN-06-1570 contributor: fullname: Kah – volume: 23 start-page: 1538 year: 2018 ident: 10.1016/j.bmcl.2018.11.001_b0105 article-title: Crystal Structure of LSD1 in complex with 4-[5-(Piperidin-4-ylmethoxy)-2-(p-tolyl)pyridin-3-yl]benzonitrile publication-title: Molecules doi: 10.3390/molecules23071538 contributor: fullname: Niwa – volume: 124 start-page: 151 issue: 1 year: 2014 ident: 10.1016/j.bmcl.2018.11.001_b0030 article-title: Lysine-specific demethylase 1 (LSD1) in hematopoietic and lymphoid neoplasms publication-title: Blood doi: 10.1182/blood-2014-04-569525 contributor: fullname: Niebel – volume: 502 start-page: 480 issue: 7472 year: 2013 ident: 10.1016/j.bmcl.2018.11.001_b0015 article-title: Chromatin proteins and modifications as drug targets publication-title: Nature doi: 10.1038/nature12751 contributor: fullname: Helin – volume: 9 start-page: 1123 issue: 8 year: 2017 ident: 10.1016/j.bmcl.2018.11.001_b0025 article-title: A comprehensive review of lysine-specific demethylase 1 and its roles in cancer publication-title: Epigenomics doi: 10.2217/epi-2017-0022 contributor: fullname: Hosseini – volume: 11 start-page: 131 year: 2017 ident: 10.1016/j.bmcl.2018.11.001_b0035 article-title: Targeting histone methyltransferase and demethylase in acute myeloid leukemia therapy publication-title: Onco Targets Ther doi: 10.2147/OTT.S145971 contributor: fullname: Castelli – ident: 10.1016/j.bmcl.2018.11.001_b0115 – volume: 119 start-page: 941 issue: 7 year: 2004 ident: 10.1016/j.bmcl.2018.11.001_b0020 article-title: Histone demethylation mediated by the nuclear amine oxidase homolog LSD1 publication-title: Cell. doi: 10.1016/j.cell.2004.12.012 contributor: fullname: Shi – volume: 71 start-page: 4192 issue: 12 year: 2011 ident: 10.1016/j.bmcl.2018.11.001_b0055 article-title: Inhibition of histone lysine methylation enhances cancer-testis antigen expression in lung cancer cells: implications for adoptive immunotherapy of cancer publication-title: Cancer Res doi: 10.1158/0008-5472.CAN-10-2442 contributor: fullname: Rao – volume: 31 start-page: 512 issue: 3 year: 2010 ident: 10.1016/j.bmcl.2018.11.001_b0050 article-title: Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology publication-title: Carcinogenesis doi: 10.1093/carcin/bgp324 contributor: fullname: Lim – volume: 60 start-page: 7984 issue: 19 year: 2017 ident: 10.1016/j.bmcl.2018.11.001_b0085 article-title: Development of (4-Cyanophenyl)glycine derivatives as reversible inhibitors of lysine specific demethylase 1 publication-title: J Med Chem doi: 10.1021/acs.jmedchem.7b00462 contributor: fullname: Mould – volume: 9 start-page: 1227 issue: 11 year: 2017 ident: 10.1016/j.bmcl.2018.11.001_b0070 article-title: Advances toward LSD1 inhibitors for cancer therapy publication-title: Future Med Chem doi: 10.4155/fmc-2017-0068 contributor: fullname: Fu – volume: 81 start-page: 303 issue: 4 year: 2012 ident: 10.1016/j.bmcl.2018.11.001_b0005 article-title: Epigenetic modifications in cancer publication-title: Clin Genet doi: 10.1111/j.1399-0004.2011.01809.x contributor: fullname: Kanwal – volume: 48 start-page: 491 issue: 4 year: 2012 ident: 10.1016/j.bmcl.2018.11.001_b0010 article-title: Histone lysine methylation dynamics: establishment, regulation, and biological impact publication-title: Mol Cell doi: 10.1016/j.molcel.2012.11.006 contributor: fullname: Black – volume: 109 start-page: 994 issue: 4 year: 2013 ident: 10.1016/j.bmcl.2018.11.001_b0065 article-title: LSD1-mediated epigenetic modification contributes to proliferation and metastasis of colon cancer publication-title: Br J Cancer doi: 10.1038/bjc.2013.364 contributor: fullname: Ding – volume: 49 start-page: 5029 issue: 17 year: 2006 ident: 10.1016/j.bmcl.2018.11.001_b0110 article-title: Medicinal chemistry of hERG optimizations: highlights and hang-ups publication-title: J Med Chem doi: 10.1021/jm060379l contributor: fullname: Jamieson – start-page: 18 year: 2015 ident: 10.1016/j.bmcl.2018.11.001_b0095 contributor: fullname: Thomas – volume: 605 year: 2012 ident: 10.1016/j.bmcl.2018.11.001_b0100 article-title: Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia publication-title: Nat Med contributor: fullname: Schenk |
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•A series of highly potent and selective reversible LSD1 inhibitors were discovered employing structure-based drug design.•Potent induction... The histone demethylase LSD1 is a key enzyme in the epigenetic regulation of gene transcription. Here we present our efforts to discover small molecule... |
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SubjectTerms | Chemistry Chemistry, Medicinal Chemistry, Organic Demethylase Epigenetics Life Sciences & Biomedicine LSD1 Lysine-specific demethylase 1 Pharmacology & Pharmacy Physical Sciences Science & Technology Structure-based drug design |
Title | Structure-based design and discovery of potent and selective lysine-specific demethylase 1 (LSD1) inhibitors |
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