ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the Treatment of Acute Leukemia
The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in A...
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| Veröffentlicht in: | Cancer cell 2018-03, Vol.33 (3), p.495-511.e12 |
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| creator | Maes, Tamara Mascaró, Cristina Tirapu, Iñigo Estiarte, Angels Ciceri, Filippo Lunardi, Serena Guibourt, Nathalie Perdones, Alvaro Lufino, Michele M.P. Somervaille, Tim C.P. Wiseman, Dan H. Duy, Cihangir Melnick, Ari Willekens, Christophe Ortega, Alberto Martinell, Marc Valls, Nuria Kurz, Guido Fyfe, Matthew Castro-Palomino, Julio Cesar Buesa, Carlos |
| description | The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia. Surrogate pharmacodynamic biomarkers developed based on expression changes in leukemia cell lines were translated to samples from patients treated with ORY-1001. ORY-1001 is a selective KDM1A inhibitor in clinical trials and is currently being evaluated in patients with leukemia and solid tumors.
•ORY-1001 is a highly potent and selective clinical stage KDM1A inhibitor•ORY-1001 induces differentiation and compromises leukemic stem cell activity in AML•Chemoproteomics elucidates native KDM1A complexes in AML cells•Gene expression profiling yields a tool for evaluation of clinical samples
Maes et al. develop ORY-1001, a highly potent and selective inhibitor of KDM1A/LSD1. ORY-1001 induces differentiation of leukemic cells in cell lines, primary AML samples, and AML patients. ORY-1001 is able to decrease leukemic growth and prolong survival of mouse models of acute leukemia. |
| doi_str_mv | 10.1016/j.ccell.2018.02.002 |
| format | Article |
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•ORY-1001 is a highly potent and selective clinical stage KDM1A inhibitor•ORY-1001 induces differentiation and compromises leukemic stem cell activity in AML•Chemoproteomics elucidates native KDM1A complexes in AML cells•Gene expression profiling yields a tool for evaluation of clinical samples
Maes et al. develop ORY-1001, a highly potent and selective inhibitor of KDM1A/LSD1. ORY-1001 induces differentiation of leukemic cells in cell lines, primary AML samples, and AML patients. ORY-1001 is able to decrease leukemic growth and prolong survival of mouse models of acute leukemia.</description><identifier>ISSN: 1535-6108</identifier><identifier>EISSN: 1878-3686</identifier><identifier>DOI: 10.1016/j.ccell.2018.02.002</identifier><identifier>PMID: 29502954</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>acute myeloid leukemia ; Animals ; Apoptosis - drug effects ; Cell Differentiation - drug effects ; Cell Line, Tumor - metabolism ; differentiation ; Disease Models, Animal ; epigenetic ; Histone Demethylases - antagonists & inhibitors ; Histone Demethylases - drug effects ; Histone Demethylases - genetics ; histone methylation ; Humans ; KDM1A ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - genetics ; LSD1 ; Mice ; ORY-1001 ; Stem Cells - drug effects ; Stem Cells - metabolism</subject><ispartof>Cancer cell, 2018-03, Vol.33 (3), p.495-511.e12</ispartof><rights>2018 Elsevier Inc.</rights><rights>Copyright © 2018 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c520t-5bd2d010b517672e09a0a1e2a58bc6970412aaa94439690fddcf3e8ed8a25a943</citedby><cites>FETCH-LOGICAL-c520t-5bd2d010b517672e09a0a1e2a58bc6970412aaa94439690fddcf3e8ed8a25a943</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ccell.2018.02.002$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29502954$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Maes, Tamara</creatorcontrib><creatorcontrib>Mascaró, Cristina</creatorcontrib><creatorcontrib>Tirapu, Iñigo</creatorcontrib><creatorcontrib>Estiarte, Angels</creatorcontrib><creatorcontrib>Ciceri, Filippo</creatorcontrib><creatorcontrib>Lunardi, Serena</creatorcontrib><creatorcontrib>Guibourt, Nathalie</creatorcontrib><creatorcontrib>Perdones, Alvaro</creatorcontrib><creatorcontrib>Lufino, Michele M.P.</creatorcontrib><creatorcontrib>Somervaille, Tim C.P.</creatorcontrib><creatorcontrib>Wiseman, Dan H.</creatorcontrib><creatorcontrib>Duy, Cihangir</creatorcontrib><creatorcontrib>Melnick, Ari</creatorcontrib><creatorcontrib>Willekens, Christophe</creatorcontrib><creatorcontrib>Ortega, Alberto</creatorcontrib><creatorcontrib>Martinell, Marc</creatorcontrib><creatorcontrib>Valls, Nuria</creatorcontrib><creatorcontrib>Kurz, Guido</creatorcontrib><creatorcontrib>Fyfe, Matthew</creatorcontrib><creatorcontrib>Castro-Palomino, Julio Cesar</creatorcontrib><creatorcontrib>Buesa, Carlos</creatorcontrib><title>ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the Treatment of Acute Leukemia</title><title>Cancer cell</title><addtitle>Cancer Cell</addtitle><description>The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia. Surrogate pharmacodynamic biomarkers developed based on expression changes in leukemia cell lines were translated to samples from patients treated with ORY-1001. ORY-1001 is a selective KDM1A inhibitor in clinical trials and is currently being evaluated in patients with leukemia and solid tumors.
•ORY-1001 is a highly potent and selective clinical stage KDM1A inhibitor•ORY-1001 induces differentiation and compromises leukemic stem cell activity in AML•Chemoproteomics elucidates native KDM1A complexes in AML cells•Gene expression profiling yields a tool for evaluation of clinical samples
Maes et al. develop ORY-1001, a highly potent and selective inhibitor of KDM1A/LSD1. ORY-1001 induces differentiation of leukemic cells in cell lines, primary AML samples, and AML patients. ORY-1001 is able to decrease leukemic growth and prolong survival of mouse models of acute leukemia.</description><subject>acute myeloid leukemia</subject><subject>Animals</subject><subject>Apoptosis - drug effects</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell Line, Tumor - metabolism</subject><subject>differentiation</subject><subject>Disease Models, Animal</subject><subject>epigenetic</subject><subject>Histone Demethylases - antagonists & inhibitors</subject><subject>Histone Demethylases - drug effects</subject><subject>Histone Demethylases - genetics</subject><subject>histone methylation</subject><subject>Humans</subject><subject>KDM1A</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>LSD1</subject><subject>Mice</subject><subject>ORY-1001</subject><subject>Stem Cells - drug effects</subject><subject>Stem Cells - metabolism</subject><issn>1535-6108</issn><issn>1878-3686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1v1DAQhi1ERT_gFyAhHzk0YeysE-fAYbVQqFhURNsDFyzHnqhekri1nZX49zhs4diDZWv8vDOah5DXDEoGrH63K43BYSg5MFkCLwH4M3LCZCOLqpb18_wWlShqBvKYnMa4g5xiTfuCHPNWQD6rE_Lz6vuPguWfc6rpN59wSlRPll7jgCa5PdKN3-thKX_58JWt6eV05zqXfDinvQ803SG9CajTuCC-p2szJ6RbnH_h6PRLctTrIeKrx_uM3F58vNl8LrZXny43621hBIdUiM5yCww6wZq64QitBs2QayE7U7cNrBjXWrerVdXWLfTWmr5CiVZqLnK5OiNvD33vg3-YMSY1urjY0RP6OarsCGTVclFltDqgJvgYA_bqPrhRh9-KgVrEqp36K3YJSQVcZbE59eZxwNyNaP9n_pnMwPsDgHnNvcOgonE4GbQuZJPKevfkgD9QJYev</recordid><startdate>20180312</startdate><enddate>20180312</enddate><creator>Maes, Tamara</creator><creator>Mascaró, Cristina</creator><creator>Tirapu, Iñigo</creator><creator>Estiarte, Angels</creator><creator>Ciceri, Filippo</creator><creator>Lunardi, Serena</creator><creator>Guibourt, Nathalie</creator><creator>Perdones, Alvaro</creator><creator>Lufino, Michele M.P.</creator><creator>Somervaille, Tim C.P.</creator><creator>Wiseman, Dan H.</creator><creator>Duy, Cihangir</creator><creator>Melnick, Ari</creator><creator>Willekens, Christophe</creator><creator>Ortega, Alberto</creator><creator>Martinell, Marc</creator><creator>Valls, Nuria</creator><creator>Kurz, Guido</creator><creator>Fyfe, Matthew</creator><creator>Castro-Palomino, Julio Cesar</creator><creator>Buesa, Carlos</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20180312</creationdate><title>ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the Treatment of Acute Leukemia</title><author>Maes, Tamara ; Mascaró, Cristina ; Tirapu, Iñigo ; Estiarte, Angels ; Ciceri, Filippo ; Lunardi, Serena ; Guibourt, Nathalie ; Perdones, Alvaro ; Lufino, Michele M.P. ; Somervaille, Tim C.P. ; Wiseman, Dan H. ; Duy, Cihangir ; Melnick, Ari ; Willekens, Christophe ; Ortega, Alberto ; Martinell, Marc ; Valls, Nuria ; Kurz, Guido ; Fyfe, Matthew ; Castro-Palomino, Julio Cesar ; Buesa, Carlos</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c520t-5bd2d010b517672e09a0a1e2a58bc6970412aaa94439690fddcf3e8ed8a25a943</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>acute myeloid leukemia</topic><topic>Animals</topic><topic>Apoptosis - drug effects</topic><topic>Cell Differentiation - drug effects</topic><topic>Cell Line, Tumor - metabolism</topic><topic>differentiation</topic><topic>Disease Models, Animal</topic><topic>epigenetic</topic><topic>Histone Demethylases - antagonists & inhibitors</topic><topic>Histone Demethylases - drug effects</topic><topic>Histone Demethylases - genetics</topic><topic>histone methylation</topic><topic>Humans</topic><topic>KDM1A</topic><topic>Leukemia, Myeloid, Acute - drug therapy</topic><topic>Leukemia, Myeloid, Acute - genetics</topic><topic>LSD1</topic><topic>Mice</topic><topic>ORY-1001</topic><topic>Stem Cells - drug effects</topic><topic>Stem Cells - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Maes, Tamara</creatorcontrib><creatorcontrib>Mascaró, Cristina</creatorcontrib><creatorcontrib>Tirapu, Iñigo</creatorcontrib><creatorcontrib>Estiarte, Angels</creatorcontrib><creatorcontrib>Ciceri, Filippo</creatorcontrib><creatorcontrib>Lunardi, Serena</creatorcontrib><creatorcontrib>Guibourt, Nathalie</creatorcontrib><creatorcontrib>Perdones, Alvaro</creatorcontrib><creatorcontrib>Lufino, Michele M.P.</creatorcontrib><creatorcontrib>Somervaille, Tim C.P.</creatorcontrib><creatorcontrib>Wiseman, Dan H.</creatorcontrib><creatorcontrib>Duy, Cihangir</creatorcontrib><creatorcontrib>Melnick, Ari</creatorcontrib><creatorcontrib>Willekens, Christophe</creatorcontrib><creatorcontrib>Ortega, Alberto</creatorcontrib><creatorcontrib>Martinell, Marc</creatorcontrib><creatorcontrib>Valls, Nuria</creatorcontrib><creatorcontrib>Kurz, Guido</creatorcontrib><creatorcontrib>Fyfe, Matthew</creatorcontrib><creatorcontrib>Castro-Palomino, Julio Cesar</creatorcontrib><creatorcontrib>Buesa, Carlos</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Maes, Tamara</au><au>Mascaró, Cristina</au><au>Tirapu, Iñigo</au><au>Estiarte, Angels</au><au>Ciceri, Filippo</au><au>Lunardi, Serena</au><au>Guibourt, Nathalie</au><au>Perdones, Alvaro</au><au>Lufino, Michele M.P.</au><au>Somervaille, Tim C.P.</au><au>Wiseman, Dan H.</au><au>Duy, Cihangir</au><au>Melnick, Ari</au><au>Willekens, Christophe</au><au>Ortega, Alberto</au><au>Martinell, Marc</au><au>Valls, Nuria</au><au>Kurz, Guido</au><au>Fyfe, Matthew</au><au>Castro-Palomino, Julio Cesar</au><au>Buesa, Carlos</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the Treatment of Acute Leukemia</atitle><jtitle>Cancer cell</jtitle><addtitle>Cancer Cell</addtitle><date>2018-03-12</date><risdate>2018</risdate><volume>33</volume><issue>3</issue><spage>495</spage><epage>511.e12</epage><pages>495-511.e12</pages><issn>1535-6108</issn><eissn>1878-3686</eissn><abstract>The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia. Surrogate pharmacodynamic biomarkers developed based on expression changes in leukemia cell lines were translated to samples from patients treated with ORY-1001. ORY-1001 is a selective KDM1A inhibitor in clinical trials and is currently being evaluated in patients with leukemia and solid tumors.
•ORY-1001 is a highly potent and selective clinical stage KDM1A inhibitor•ORY-1001 induces differentiation and compromises leukemic stem cell activity in AML•Chemoproteomics elucidates native KDM1A complexes in AML cells•Gene expression profiling yields a tool for evaluation of clinical samples
Maes et al. develop ORY-1001, a highly potent and selective inhibitor of KDM1A/LSD1. ORY-1001 induces differentiation of leukemic cells in cell lines, primary AML samples, and AML patients. ORY-1001 is able to decrease leukemic growth and prolong survival of mouse models of acute leukemia.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>29502954</pmid><doi>10.1016/j.ccell.2018.02.002</doi><oa>free_for_read</oa></addata></record> |
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| subjects | acute myeloid leukemia Animals Apoptosis - drug effects Cell Differentiation - drug effects Cell Line, Tumor - metabolism differentiation Disease Models, Animal epigenetic Histone Demethylases - antagonists & inhibitors Histone Demethylases - drug effects Histone Demethylases - genetics histone methylation Humans KDM1A Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - genetics LSD1 Mice ORY-1001 Stem Cells - drug effects Stem Cells - metabolism |
| title | ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the Treatment of Acute Leukemia |
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