The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K
Irreversible covalent inhibitors can have a beneficial pharmacokinetic/pharmacodynamics profile but are still often avoided due to the risk of indiscriminate covalent reactivity and the resulting adverse effects. To overcome this potential liability, we introduced an alkyne moiety as a latent electr...
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| Veröffentlicht in: | Journal of the American Chemical Society 2019-02, Vol.141 (8), p.3507-3514 |
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| creator | Mons, Elma Jansen, Ineke D. C Loboda, Jure van Doodewaerd, Bjorn R Hermans, Jill Verdoes, Martijn van Boeckel, Constant A. A van Veelen, Peter A Turk, Boris Turk, Dusan Ovaa, Huib |
| description | Irreversible covalent inhibitors can have a beneficial pharmacokinetic/pharmacodynamics profile but are still often avoided due to the risk of indiscriminate covalent reactivity and the resulting adverse effects. To overcome this potential liability, we introduced an alkyne moiety as a latent electrophile into small molecule inhibitors of cathepsin K (CatK). Alkyne-based inhibitors do not show indiscriminate thiol reactivity but potently inhibit CatK protease activity by formation of an irreversible covalent bond with the catalytic cysteine residue, confirmed by crystal structure analysis. The rate of covalent bond formation (k inact) does not correlate with electrophilicity of the alkyne moiety, indicative of a proximity-driven reactivity. Inhibition of CatK-mediated bone resorption is validated in human osteoclasts. Together, this work illustrates the potential of alkynes as latent electrophiles in small molecule inhibitors, enabling the development of irreversible covalent inhibitors with an improved safety profile. |
| doi_str_mv | 10.1021/jacs.8b11027 |
| format | Article |
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C ; Loboda, Jure ; van Doodewaerd, Bjorn R ; Hermans, Jill ; Verdoes, Martijn ; van Boeckel, Constant A. A ; van Veelen, Peter A ; Turk, Boris ; Turk, Dusan ; Ovaa, Huib</creator><creatorcontrib>Mons, Elma ; Jansen, Ineke D. C ; Loboda, Jure ; van Doodewaerd, Bjorn R ; Hermans, Jill ; Verdoes, Martijn ; van Boeckel, Constant A. A ; van Veelen, Peter A ; Turk, Boris ; Turk, Dusan ; Ovaa, Huib</creatorcontrib><description>Irreversible covalent inhibitors can have a beneficial pharmacokinetic/pharmacodynamics profile but are still often avoided due to the risk of indiscriminate covalent reactivity and the resulting adverse effects. To overcome this potential liability, we introduced an alkyne moiety as a latent electrophile into small molecule inhibitors of cathepsin K (CatK). Alkyne-based inhibitors do not show indiscriminate thiol reactivity but potently inhibit CatK protease activity by formation of an irreversible covalent bond with the catalytic cysteine residue, confirmed by crystal structure analysis. The rate of covalent bond formation (k inact) does not correlate with electrophilicity of the alkyne moiety, indicative of a proximity-driven reactivity. Inhibition of CatK-mediated bone resorption is validated in human osteoclasts. Together, this work illustrates the potential of alkynes as latent electrophiles in small molecule inhibitors, enabling the development of irreversible covalent inhibitors with an improved safety profile.</description><identifier>ISSN: 0002-7863</identifier><identifier>ISSN: 1520-5126</identifier><identifier>EISSN: 1520-5126</identifier><identifier>DOI: 10.1021/jacs.8b11027</identifier><identifier>PMID: 30689386</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>adverse effects ; alkynes ; Alkynes - chemistry ; Alkynes - pharmacology ; bone resorption ; cathepsin K ; Cathepsin K - antagonists & inhibitors ; Cathepsin K - metabolism ; chemical bonding ; crystal structure ; cysteine ; Cysteine Proteinase Inhibitors - chemical synthesis ; Cysteine Proteinase Inhibitors - chemistry ; Cysteine Proteinase Inhibitors - pharmacology ; enzyme activity ; Humans ; Lewis acids ; Models, Molecular ; moieties ; Molecular Structure ; osteoclasts ; pharmacodynamics ; pharmacokinetics ; risk ; Small Molecule Libraries - chemical synthesis ; Small Molecule Libraries - chemistry ; Small Molecule Libraries - pharmacology ; thiols</subject><ispartof>Journal of the American Chemical Society, 2019-02, Vol.141 (8), p.3507-3514</ispartof><rights>Copyright © 2019 American Chemical Society 2019 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a542t-6218e7153e7d5511b65bd6f83db4e936ce880ad7707128eee7762dc7b3b92d793</citedby><cites>FETCH-LOGICAL-a542t-6218e7153e7d5511b65bd6f83db4e936ce880ad7707128eee7762dc7b3b92d793</cites><orcidid>0000-0003-1105-6424 ; 0000-0001-8753-3528 ; 0000-0002-0068-054X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jacs.8b11027$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jacs.8b11027$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30689386$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mons, Elma</creatorcontrib><creatorcontrib>Jansen, Ineke D. C</creatorcontrib><creatorcontrib>Loboda, Jure</creatorcontrib><creatorcontrib>van Doodewaerd, Bjorn R</creatorcontrib><creatorcontrib>Hermans, Jill</creatorcontrib><creatorcontrib>Verdoes, Martijn</creatorcontrib><creatorcontrib>van Boeckel, Constant A. A</creatorcontrib><creatorcontrib>van Veelen, Peter A</creatorcontrib><creatorcontrib>Turk, Boris</creatorcontrib><creatorcontrib>Turk, Dusan</creatorcontrib><creatorcontrib>Ovaa, Huib</creatorcontrib><title>The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K</title><title>Journal of the American Chemical Society</title><addtitle>J. Am. Chem. Soc</addtitle><description>Irreversible covalent inhibitors can have a beneficial pharmacokinetic/pharmacodynamics profile but are still often avoided due to the risk of indiscriminate covalent reactivity and the resulting adverse effects. To overcome this potential liability, we introduced an alkyne moiety as a latent electrophile into small molecule inhibitors of cathepsin K (CatK). Alkyne-based inhibitors do not show indiscriminate thiol reactivity but potently inhibit CatK protease activity by formation of an irreversible covalent bond with the catalytic cysteine residue, confirmed by crystal structure analysis. The rate of covalent bond formation (k inact) does not correlate with electrophilicity of the alkyne moiety, indicative of a proximity-driven reactivity. Inhibition of CatK-mediated bone resorption is validated in human osteoclasts. Together, this work illustrates the potential of alkynes as latent electrophiles in small molecule inhibitors, enabling the development of irreversible covalent inhibitors with an improved safety profile.</description><subject>adverse effects</subject><subject>alkynes</subject><subject>Alkynes - chemistry</subject><subject>Alkynes - pharmacology</subject><subject>bone resorption</subject><subject>cathepsin K</subject><subject>Cathepsin K - antagonists & inhibitors</subject><subject>Cathepsin K - metabolism</subject><subject>chemical bonding</subject><subject>crystal structure</subject><subject>cysteine</subject><subject>Cysteine Proteinase Inhibitors - chemical synthesis</subject><subject>Cysteine Proteinase Inhibitors - chemistry</subject><subject>Cysteine Proteinase Inhibitors - pharmacology</subject><subject>enzyme activity</subject><subject>Humans</subject><subject>Lewis acids</subject><subject>Models, Molecular</subject><subject>moieties</subject><subject>Molecular Structure</subject><subject>osteoclasts</subject><subject>pharmacodynamics</subject><subject>pharmacokinetics</subject><subject>risk</subject><subject>Small Molecule Libraries - chemical synthesis</subject><subject>Small Molecule Libraries - chemistry</subject><subject>Small Molecule Libraries - pharmacology</subject><subject>thiols</subject><issn>0002-7863</issn><issn>1520-5126</issn><issn>1520-5126</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1PGzEQxS3UqqS0N87Ixx5Y8Ef8sRckFAGNmqqH0rNl7066Ds46tXcj5b_HESkFCakn69m_eTOeh9ApJReUMHq5sk2-0I4WoY7QhApGKkGZfIcmhBBWKS35MfqY86rIKdP0AzrmROqaazlB4b4DfB0edj3g79HDsMM2Y4sXdoB-wDcBmiHFTecDYN_jeUqwhZS9K3oWtzbsqZ9rG0IpL_BY7ud9550fYso4LvHMDh1scin-9gm9X9qQ4fPhPEG_bm_uZ1-rxY-7-ex6UVkxZUMlGdWgqOCgWiEodVK4Vi41b90Uai4b0JrYVimiKNMAoJRkbaMcdzVrVc1P0NWT72Z0a2ibMmOywWySX9u0M9F68_ql9535HbdG8lpyqovBl4NBin9GyINZ-9xACLaHOGbDGFeCi7Le_6NU1VNNFecFPX9CmxRzTrB8nogSs8_S7LM0hywLfvbyF8_w3_D-td5XreKY-rLUt70eASKTqHU</recordid><startdate>20190227</startdate><enddate>20190227</enddate><creator>Mons, Elma</creator><creator>Jansen, Ineke D. C</creator><creator>Loboda, Jure</creator><creator>van Doodewaerd, Bjorn R</creator><creator>Hermans, Jill</creator><creator>Verdoes, Martijn</creator><creator>van Boeckel, Constant A. A</creator><creator>van Veelen, Peter A</creator><creator>Turk, Boris</creator><creator>Turk, Dusan</creator><creator>Ovaa, Huib</creator><general>American Chemical Society</general><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><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-1105-6424</orcidid><orcidid>https://orcid.org/0000-0001-8753-3528</orcidid><orcidid>https://orcid.org/0000-0002-0068-054X</orcidid></search><sort><creationdate>20190227</creationdate><title>The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K</title><author>Mons, Elma ; Jansen, Ineke D. C ; Loboda, Jure ; van Doodewaerd, Bjorn R ; Hermans, Jill ; Verdoes, Martijn ; van Boeckel, Constant A. A ; van Veelen, Peter A ; Turk, Boris ; Turk, Dusan ; Ovaa, Huib</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a542t-6218e7153e7d5511b65bd6f83db4e936ce880ad7707128eee7762dc7b3b92d793</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>adverse effects</topic><topic>alkynes</topic><topic>Alkynes - chemistry</topic><topic>Alkynes - pharmacology</topic><topic>bone resorption</topic><topic>cathepsin K</topic><topic>Cathepsin K - antagonists & inhibitors</topic><topic>Cathepsin K - metabolism</topic><topic>chemical bonding</topic><topic>crystal structure</topic><topic>cysteine</topic><topic>Cysteine Proteinase Inhibitors - chemical synthesis</topic><topic>Cysteine Proteinase Inhibitors - chemistry</topic><topic>Cysteine Proteinase Inhibitors - pharmacology</topic><topic>enzyme activity</topic><topic>Humans</topic><topic>Lewis acids</topic><topic>Models, Molecular</topic><topic>moieties</topic><topic>Molecular Structure</topic><topic>osteoclasts</topic><topic>pharmacodynamics</topic><topic>pharmacokinetics</topic><topic>risk</topic><topic>Small Molecule Libraries - chemical synthesis</topic><topic>Small Molecule Libraries - chemistry</topic><topic>Small Molecule Libraries - pharmacology</topic><topic>thiols</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mons, Elma</creatorcontrib><creatorcontrib>Jansen, Ineke D. 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A</creatorcontrib><creatorcontrib>van Veelen, Peter A</creatorcontrib><creatorcontrib>Turk, Boris</creatorcontrib><creatorcontrib>Turk, Dusan</creatorcontrib><creatorcontrib>Ovaa, Huib</creatorcontrib><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><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of the American Chemical Society</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mons, Elma</au><au>Jansen, Ineke D. C</au><au>Loboda, Jure</au><au>van Doodewaerd, Bjorn R</au><au>Hermans, Jill</au><au>Verdoes, Martijn</au><au>van Boeckel, Constant A. 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Alkyne-based inhibitors do not show indiscriminate thiol reactivity but potently inhibit CatK protease activity by formation of an irreversible covalent bond with the catalytic cysteine residue, confirmed by crystal structure analysis. The rate of covalent bond formation (k inact) does not correlate with electrophilicity of the alkyne moiety, indicative of a proximity-driven reactivity. Inhibition of CatK-mediated bone resorption is validated in human osteoclasts. 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| subjects | adverse effects alkynes Alkynes - chemistry Alkynes - pharmacology bone resorption cathepsin K Cathepsin K - antagonists & inhibitors Cathepsin K - metabolism chemical bonding crystal structure cysteine Cysteine Proteinase Inhibitors - chemical synthesis Cysteine Proteinase Inhibitors - chemistry Cysteine Proteinase Inhibitors - pharmacology enzyme activity Humans Lewis acids Models, Molecular moieties Molecular Structure osteoclasts pharmacodynamics pharmacokinetics risk Small Molecule Libraries - chemical synthesis Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology thiols |
| title | The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K |
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