Structural Basis of Nanomolar Inhibition of Tumor-Associated Carbonic Anhydrase IX: X‑Ray Crystallographic and Inhibition Study of Lipophilic Inhibitors with Acetazolamide Backbone
This study provides a structure–activity relationship study of a series of lipophilic carbonic anhydrase (CA) inhibitors with an acetazolamide backbone. The inhibitors were tested against the tumor-expressed CA isozyme IX (CA IX), and the cytosolic CA I, CA II, and membrane-bound CA IV. The study id...
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| Veröffentlicht in: | Journal of medicinal chemistry 2020-11, Vol.63 (21), p.13064-13075 |
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| container_issue | 21 |
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| container_title | Journal of medicinal chemistry |
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| creator | Andring, Jacob T Fouch, Mallorie Akocak, Suleyman Angeli, Andrea Supuran, Claudiu T Ilies, Marc A McKenna, Robert |
| description | This study provides a structure–activity relationship study of a series of lipophilic carbonic anhydrase (CA) inhibitors with an acetazolamide backbone. The inhibitors were tested against the tumor-expressed CA isozyme IX (CA IX), and the cytosolic CA I, CA II, and membrane-bound CA IV. The study identified several low nanomolar potent inhibitors against CA IX, with lipophilicities spanning two log units. Very potent pan-inhibitors with nanomolar potency against CA IX and sub-nanomolar potency against CA II and CA IV, and with potency against CA I one order of magnitude better than the parent acetazolamide 1 were also identified in this study, together with compounds that displayed selectivity against membrane-bound CA IV. A comprehensive X-ray crystallographic study (12 crystal structures), involving both CA II and a soluble CA IX mimetic (CA IX-mimic), revealed the structural basis of this particular inhibition profile and laid the foundation for further developments toward more potent and selective inhibitors for the tumor-expressed CA IX. |
| doi_str_mv | 10.1021/acs.jmedchem.0c01390 |
| format | Article |
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The inhibitors were tested against the tumor-expressed CA isozyme IX (CA IX), and the cytosolic CA I, CA II, and membrane-bound CA IV. The study identified several low nanomolar potent inhibitors against CA IX, with lipophilicities spanning two log units. Very potent pan-inhibitors with nanomolar potency against CA IX and sub-nanomolar potency against CA II and CA IV, and with potency against CA I one order of magnitude better than the parent acetazolamide 1 were also identified in this study, together with compounds that displayed selectivity against membrane-bound CA IV. A comprehensive X-ray crystallographic study (12 crystal structures), involving both CA II and a soluble CA IX mimetic (CA IX-mimic), revealed the structural basis of this particular inhibition profile and laid the foundation for further developments toward more potent and selective inhibitors for the tumor-expressed CA IX.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.0c01390</identifier><identifier>PMID: 33085484</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Acetazolamide - chemistry ; Acetazolamide - metabolism ; Binding Sites ; Carbonic Anhydrase Inhibitors - chemistry ; Carbonic Anhydrase Inhibitors - metabolism ; Carbonic Anhydrase IX - antagonists & inhibitors ; Carbonic Anhydrase IX - genetics ; Carbonic Anhydrase IX - metabolism ; Catalytic Domain ; Crystallography, X-Ray ; Humans ; Hydrophobic and Hydrophilic Interactions ; Isoenzymes - antagonists & inhibitors ; Isoenzymes - genetics ; Isoenzymes - metabolism ; Molecular Dynamics Simulation ; Neoplasms - enzymology ; Neoplasms - pathology ; Recombinant Proteins - biosynthesis ; Recombinant Proteins - chemistry ; Recombinant Proteins - isolation & purification ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2020-11, Vol.63 (21), p.13064-13075</ispartof><rights>2020 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a348t-757ec7806c25ef8160dc15a94b3c5e0bffc033e4e448edaa3779e89893f10d293</citedby><cites>FETCH-LOGICAL-a348t-757ec7806c25ef8160dc15a94b3c5e0bffc033e4e448edaa3779e89893f10d293</cites><orcidid>0000-0003-4262-0323 ; 0000-0002-1470-7192 ; 0000-0002-6632-6391 ; 0000-0003-0694-411X</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/acs.jmedchem.0c01390$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.0c01390$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33085484$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Andring, Jacob T</creatorcontrib><creatorcontrib>Fouch, Mallorie</creatorcontrib><creatorcontrib>Akocak, Suleyman</creatorcontrib><creatorcontrib>Angeli, Andrea</creatorcontrib><creatorcontrib>Supuran, Claudiu T</creatorcontrib><creatorcontrib>Ilies, Marc A</creatorcontrib><creatorcontrib>McKenna, Robert</creatorcontrib><title>Structural Basis of Nanomolar Inhibition of Tumor-Associated Carbonic Anhydrase IX: X‑Ray Crystallographic and Inhibition Study of Lipophilic Inhibitors with Acetazolamide Backbone</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>This study provides a structure–activity relationship study of a series of lipophilic carbonic anhydrase (CA) inhibitors with an acetazolamide backbone. The inhibitors were tested against the tumor-expressed CA isozyme IX (CA IX), and the cytosolic CA I, CA II, and membrane-bound CA IV. The study identified several low nanomolar potent inhibitors against CA IX, with lipophilicities spanning two log units. Very potent pan-inhibitors with nanomolar potency against CA IX and sub-nanomolar potency against CA II and CA IV, and with potency against CA I one order of magnitude better than the parent acetazolamide 1 were also identified in this study, together with compounds that displayed selectivity against membrane-bound CA IV. A comprehensive X-ray crystallographic study (12 crystal structures), involving both CA II and a soluble CA IX mimetic (CA IX-mimic), revealed the structural basis of this particular inhibition profile and laid the foundation for further developments toward more potent and selective inhibitors for the tumor-expressed CA IX.</description><subject>Acetazolamide - chemistry</subject><subject>Acetazolamide - metabolism</subject><subject>Binding Sites</subject><subject>Carbonic Anhydrase Inhibitors - chemistry</subject><subject>Carbonic Anhydrase Inhibitors - metabolism</subject><subject>Carbonic Anhydrase IX - antagonists & inhibitors</subject><subject>Carbonic Anhydrase IX - genetics</subject><subject>Carbonic Anhydrase IX - metabolism</subject><subject>Catalytic Domain</subject><subject>Crystallography, X-Ray</subject><subject>Humans</subject><subject>Hydrophobic and Hydrophilic Interactions</subject><subject>Isoenzymes - antagonists & inhibitors</subject><subject>Isoenzymes - genetics</subject><subject>Isoenzymes - metabolism</subject><subject>Molecular Dynamics Simulation</subject><subject>Neoplasms - enzymology</subject><subject>Neoplasms - pathology</subject><subject>Recombinant Proteins - biosynthesis</subject><subject>Recombinant Proteins - chemistry</subject><subject>Recombinant Proteins - isolation & purification</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kVFu1DAQhi0EokvhBgj5AlnGsbNxeFtWha60AokWqW_RxHaISxKvbEcofeoVuEwPxEnwslvEE0-WZr7_98z8hLxmsGSQs7eowvJ2MFp1ZliCAsYreEIWrMghExLEU7IAyPMsX-X8jLwI4RYAOMv5c3LGOchCSLEgD1fRTypOHnv6HoMN1LX0E45ucD16uh0729ho3XioX0-D89k6BKcsRqPpBn3jRqvoeuxm7TEYur15R29-3f_8gjPd-DlE7Hv3zeO-SxiO-l_Lqzjp-WC8s3uXgD4hp7bzgf6wsaNrZSLepWEGq00aUX1PP5qX5FmLfTCvTu85-frh4npzme0-f9xu1rsMuZAxK4vSqFLCSuWFaSVbgVaswEo0XBUGmrZVwLkRRghpNCIvy8rISla8ZaDzip8TcfRV3oXgTVvvvR3QzzWD-hBDnWKoH2OoTzEk2ZujbD81qfdX9Hj3BMAR-CN3kx_TFv_3_A2kwZya</recordid><startdate>20201112</startdate><enddate>20201112</enddate><creator>Andring, Jacob T</creator><creator>Fouch, Mallorie</creator><creator>Akocak, Suleyman</creator><creator>Angeli, Andrea</creator><creator>Supuran, Claudiu T</creator><creator>Ilies, Marc A</creator><creator>McKenna, Robert</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><orcidid>https://orcid.org/0000-0003-4262-0323</orcidid><orcidid>https://orcid.org/0000-0002-1470-7192</orcidid><orcidid>https://orcid.org/0000-0002-6632-6391</orcidid><orcidid>https://orcid.org/0000-0003-0694-411X</orcidid></search><sort><creationdate>20201112</creationdate><title>Structural Basis of Nanomolar Inhibition of Tumor-Associated Carbonic Anhydrase IX: X‑Ray Crystallographic and Inhibition Study of Lipophilic Inhibitors with Acetazolamide Backbone</title><author>Andring, Jacob T ; Fouch, Mallorie ; Akocak, Suleyman ; Angeli, Andrea ; Supuran, Claudiu T ; Ilies, Marc A ; McKenna, Robert</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-757ec7806c25ef8160dc15a94b3c5e0bffc033e4e448edaa3779e89893f10d293</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Acetazolamide - chemistry</topic><topic>Acetazolamide - metabolism</topic><topic>Binding Sites</topic><topic>Carbonic Anhydrase Inhibitors - chemistry</topic><topic>Carbonic Anhydrase Inhibitors - metabolism</topic><topic>Carbonic Anhydrase IX - antagonists & inhibitors</topic><topic>Carbonic Anhydrase IX - genetics</topic><topic>Carbonic Anhydrase IX - metabolism</topic><topic>Catalytic Domain</topic><topic>Crystallography, X-Ray</topic><topic>Humans</topic><topic>Hydrophobic and Hydrophilic Interactions</topic><topic>Isoenzymes - antagonists & inhibitors</topic><topic>Isoenzymes - genetics</topic><topic>Isoenzymes - metabolism</topic><topic>Molecular Dynamics Simulation</topic><topic>Neoplasms - enzymology</topic><topic>Neoplasms - pathology</topic><topic>Recombinant Proteins - biosynthesis</topic><topic>Recombinant Proteins - chemistry</topic><topic>Recombinant Proteins - isolation & purification</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Andring, Jacob T</creatorcontrib><creatorcontrib>Fouch, Mallorie</creatorcontrib><creatorcontrib>Akocak, Suleyman</creatorcontrib><creatorcontrib>Angeli, Andrea</creatorcontrib><creatorcontrib>Supuran, Claudiu T</creatorcontrib><creatorcontrib>Ilies, Marc A</creatorcontrib><creatorcontrib>McKenna, Robert</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Andring, Jacob T</au><au>Fouch, Mallorie</au><au>Akocak, Suleyman</au><au>Angeli, Andrea</au><au>Supuran, Claudiu T</au><au>Ilies, Marc A</au><au>McKenna, Robert</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural Basis of Nanomolar Inhibition of Tumor-Associated Carbonic Anhydrase IX: X‑Ray Crystallographic and Inhibition Study of Lipophilic Inhibitors with Acetazolamide Backbone</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2020-11-12</date><risdate>2020</risdate><volume>63</volume><issue>21</issue><spage>13064</spage><epage>13075</epage><pages>13064-13075</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>This study provides a structure–activity relationship study of a series of lipophilic carbonic anhydrase (CA) inhibitors with an acetazolamide backbone. The inhibitors were tested against the tumor-expressed CA isozyme IX (CA IX), and the cytosolic CA I, CA II, and membrane-bound CA IV. The study identified several low nanomolar potent inhibitors against CA IX, with lipophilicities spanning two log units. Very potent pan-inhibitors with nanomolar potency against CA IX and sub-nanomolar potency against CA II and CA IV, and with potency against CA I one order of magnitude better than the parent acetazolamide 1 were also identified in this study, together with compounds that displayed selectivity against membrane-bound CA IV. A comprehensive X-ray crystallographic study (12 crystal structures), involving both CA II and a soluble CA IX mimetic (CA IX-mimic), revealed the structural basis of this particular inhibition profile and laid the foundation for further developments toward more potent and selective inhibitors for the tumor-expressed CA IX.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>33085484</pmid><doi>10.1021/acs.jmedchem.0c01390</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-4262-0323</orcidid><orcidid>https://orcid.org/0000-0002-1470-7192</orcidid><orcidid>https://orcid.org/0000-0002-6632-6391</orcidid><orcidid>https://orcid.org/0000-0003-0694-411X</orcidid></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2020-11, Vol.63 (21), p.13064-13075 |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Acetazolamide - chemistry Acetazolamide - metabolism Binding Sites Carbonic Anhydrase Inhibitors - chemistry Carbonic Anhydrase Inhibitors - metabolism Carbonic Anhydrase IX - antagonists & inhibitors Carbonic Anhydrase IX - genetics Carbonic Anhydrase IX - metabolism Catalytic Domain Crystallography, X-Ray Humans Hydrophobic and Hydrophilic Interactions Isoenzymes - antagonists & inhibitors Isoenzymes - genetics Isoenzymes - metabolism Molecular Dynamics Simulation Neoplasms - enzymology Neoplasms - pathology Recombinant Proteins - biosynthesis Recombinant Proteins - chemistry Recombinant Proteins - isolation & purification Structure-Activity Relationship |
| title | Structural Basis of Nanomolar Inhibition of Tumor-Associated Carbonic Anhydrase IX: X‑Ray Crystallographic and Inhibition Study of Lipophilic Inhibitors with Acetazolamide Backbone |
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