Design and Synthesis of Styrenylcyclopropylamine LSD1 Inhibitors
Leveraging the catalytic machinery of LSD1 (KDM1A), a series of covalent styrenylcyclopropane LSD1 inhibitors were identified. These inhibitors represent a new class of mechanism-based inhibitors that target and covalently label the FAD cofactor of LSD1. The series was rapidly progressed to potent b...
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| Veröffentlicht in: | ACS medicinal chemistry letters 2020-06, Vol.11 (6), p.1213-1220 |
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| creator | Gehling, Victor S McGrath, John P Duplessis, Martin Khanna, Avinash Brucelle, Francois Vaswani, Rishi G Côté, Alexandre Stuckey, Jacob Watson, Venita Cummings, Richard T Balasubramanian, Srividya Iyer, Priyadarshini Sawant, Priyanka Good, Andrew C Albrecht, Brian K Harmange, Jean-Christophe Audia, James E Bellon, Steven F Trojer, Patrick Levell, Julian R |
| description | Leveraging the catalytic machinery of LSD1 (KDM1A), a series of covalent styrenylcyclopropane LSD1 inhibitors were identified. These inhibitors represent a new class of mechanism-based inhibitors that target and covalently label the FAD cofactor of LSD1. The series was rapidly progressed to potent biochemical and cellular LSD1 inhibitors with good physical properties. This effort resulted in the identification of
, a highly potent ( |
| doi_str_mv | 10.1021/acsmedchemlett.0c00060 |
| format | Article |
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, a highly potent (<4 nM biochemical, 2 nM cell, and 1 nM GI
), and selective LSD1 inhibitor. In-depth kinetic profiling of
confirmed its covalent mechanism of action, validated the styrenylcyclopropane as an FAD-directed warhead, and demonstrated that the potency of this inhibitor is driven by improved non-covalent binding (
).
demonstrated robust cell-killing activity in a panel of AML cell lines and robust antitumor activity in a Kasumi-1 xenograft model of AML when dosed orally at 1.5 mg/kg once daily.</description><identifier>ISSN: 1948-5875</identifier><identifier>EISSN: 1948-5875</identifier><identifier>DOI: 10.1021/acsmedchemlett.0c00060</identifier><identifier>PMID: 32551003</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Letter</subject><ispartof>ACS medicinal chemistry letters, 2020-06, Vol.11 (6), p.1213-1220</ispartof><rights>Copyright © 2020 American Chemical Society.</rights><rights>Copyright © 2020 American Chemical Society 2020 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c414t-27eecbe645e4bda72aafd62d3a4848edce1db14fae474bf843381e9399d24aac3</citedby><cites>FETCH-LOGICAL-c414t-27eecbe645e4bda72aafd62d3a4848edce1db14fae474bf843381e9399d24aac3</cites><orcidid>0000-0002-6171-3819 ; 0000-0003-1741-7040 ; 0000-0003-0471-8573</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294731/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294731/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,2765,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32551003$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gehling, Victor S</creatorcontrib><creatorcontrib>McGrath, John P</creatorcontrib><creatorcontrib>Duplessis, Martin</creatorcontrib><creatorcontrib>Khanna, Avinash</creatorcontrib><creatorcontrib>Brucelle, Francois</creatorcontrib><creatorcontrib>Vaswani, Rishi G</creatorcontrib><creatorcontrib>Côté, Alexandre</creatorcontrib><creatorcontrib>Stuckey, Jacob</creatorcontrib><creatorcontrib>Watson, Venita</creatorcontrib><creatorcontrib>Cummings, Richard T</creatorcontrib><creatorcontrib>Balasubramanian, Srividya</creatorcontrib><creatorcontrib>Iyer, Priyadarshini</creatorcontrib><creatorcontrib>Sawant, Priyanka</creatorcontrib><creatorcontrib>Good, Andrew C</creatorcontrib><creatorcontrib>Albrecht, Brian K</creatorcontrib><creatorcontrib>Harmange, Jean-Christophe</creatorcontrib><creatorcontrib>Audia, James E</creatorcontrib><creatorcontrib>Bellon, Steven F</creatorcontrib><creatorcontrib>Trojer, Patrick</creatorcontrib><creatorcontrib>Levell, Julian R</creatorcontrib><title>Design and Synthesis of Styrenylcyclopropylamine LSD1 Inhibitors</title><title>ACS medicinal chemistry letters</title><addtitle>ACS Med Chem Lett</addtitle><description>Leveraging the catalytic machinery of LSD1 (KDM1A), a series of covalent styrenylcyclopropane LSD1 inhibitors were identified. These inhibitors represent a new class of mechanism-based inhibitors that target and covalently label the FAD cofactor of LSD1. The series was rapidly progressed to potent biochemical and cellular LSD1 inhibitors with good physical properties. This effort resulted in the identification of
, a highly potent (<4 nM biochemical, 2 nM cell, and 1 nM GI
), and selective LSD1 inhibitor. In-depth kinetic profiling of
confirmed its covalent mechanism of action, validated the styrenylcyclopropane as an FAD-directed warhead, and demonstrated that the potency of this inhibitor is driven by improved non-covalent binding (
).
demonstrated robust cell-killing activity in a panel of AML cell lines and robust antitumor activity in a Kasumi-1 xenograft model of AML when dosed orally at 1.5 mg/kg once daily.</description><subject>Letter</subject><issn>1948-5875</issn><issn>1948-5875</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNpVUMtOwzAQtBCIlsIvVDlySbFjJ04uCNTyqFSJQ-FsOc6mCXLsYKdI-XtStVTtaXe1M7M7g9CU4BnBEXmQyjdQqAoaDV03wwpjnOALNCYZS8M45fHlST9CN95_D4iMc3yNRjSKY4IxHaOnBfh6YwJpimDdm64aRh_YMlh3vQPTa9UrbVtn217LpjYQrNYLEixNVed1Z52_RVel1B7uDnWCvl5fPufv4erjbTl_XoWKEdaFEQdQOSQsBpYXkkdSlkUSFVSylKWDEyBFTlgpgXGWlymjNCWQ0SwrIialohP0uNdtt_nOOZjOSS1aVzfS9cLKWpxvTF2Jjf0VPMoYp2QQuD8IOPuzBd-JpvYKtJYG7NaLiJF4gFKWDdBkD1XOeu-gPJ4hWOziF-fxi0P8A3F6-uSR9p83_QO8bYiI</recordid><startdate>20200611</startdate><enddate>20200611</enddate><creator>Gehling, Victor S</creator><creator>McGrath, John P</creator><creator>Duplessis, Martin</creator><creator>Khanna, Avinash</creator><creator>Brucelle, Francois</creator><creator>Vaswani, Rishi G</creator><creator>Côté, Alexandre</creator><creator>Stuckey, Jacob</creator><creator>Watson, Venita</creator><creator>Cummings, Richard T</creator><creator>Balasubramanian, Srividya</creator><creator>Iyer, Priyadarshini</creator><creator>Sawant, Priyanka</creator><creator>Good, Andrew C</creator><creator>Albrecht, Brian K</creator><creator>Harmange, Jean-Christophe</creator><creator>Audia, James E</creator><creator>Bellon, Steven F</creator><creator>Trojer, Patrick</creator><creator>Levell, Julian R</creator><general>American Chemical Society</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6171-3819</orcidid><orcidid>https://orcid.org/0000-0003-1741-7040</orcidid><orcidid>https://orcid.org/0000-0003-0471-8573</orcidid></search><sort><creationdate>20200611</creationdate><title>Design and Synthesis of Styrenylcyclopropylamine LSD1 Inhibitors</title><author>Gehling, Victor S ; 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These inhibitors represent a new class of mechanism-based inhibitors that target and covalently label the FAD cofactor of LSD1. The series was rapidly progressed to potent biochemical and cellular LSD1 inhibitors with good physical properties. This effort resulted in the identification of
, a highly potent (<4 nM biochemical, 2 nM cell, and 1 nM GI
), and selective LSD1 inhibitor. In-depth kinetic profiling of
confirmed its covalent mechanism of action, validated the styrenylcyclopropane as an FAD-directed warhead, and demonstrated that the potency of this inhibitor is driven by improved non-covalent binding (
).
demonstrated robust cell-killing activity in a panel of AML cell lines and robust antitumor activity in a Kasumi-1 xenograft model of AML when dosed orally at 1.5 mg/kg once daily.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>32551003</pmid><doi>10.1021/acsmedchemlett.0c00060</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0002-6171-3819</orcidid><orcidid>https://orcid.org/0000-0003-1741-7040</orcidid><orcidid>https://orcid.org/0000-0003-0471-8573</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1948-5875 |
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| source | EZB-FREE-00999 freely available EZB journals; PubMed Central; American Chemical Society Journals |
| subjects | Letter |
| title | Design and Synthesis of Styrenylcyclopropylamine LSD1 Inhibitors |
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