A Selective and Orally Bioavailable Quinoline-6-Carbonitrile-Based Inhibitor of CDK8/19 Mediator Kinase with Tumor-Enriched Pharmacokinetics
Senexins are potent and selective quinazoline inhibitors of CDK8/19 Mediator kinases. To improve their potency and metabolic stability, quinoline-based derivatives were designed through a structure-guided strategy based on the simulated drug–target docking model of Senexin A and Senexin B. A library...
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| Veröffentlicht in: | Journal of medicinal chemistry 2022-02, Vol.65 (4), p.3420-3433 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 65 |
| creator | Zhang, Li Cheng, Chen Li, Jing Wang, Lili Chumanevich, Alexander A Porter, Donald C Mindich, Aleksei Gorbunova, Svetlana Roninson, Igor B Chen, Mengqian McInnes, Campbell |
| description | Senexins are potent and selective quinazoline inhibitors of CDK8/19 Mediator kinases. To improve their potency and metabolic stability, quinoline-based derivatives were designed through a structure-guided strategy based on the simulated drug–target docking model of Senexin A and Senexin B. A library of quinoline-Senexin derivatives was synthesized to explore the structure–activity relationship (SAR). An optimized compound 20a (Senexin C) exhibits potent CDK8/19 inhibitory activity with high selectivity. Senexin C is more metabolically stable and provides a more sustained inhibition of CDK8/19-dependent cellular gene expression when compared with the prototype inhibitor Senexin B. In vivo pharmacokinetic (PK) and pharmacodynamic (PD) evaluation using a novel tumor-based PD assay showed good oral bioavailability of Senexin C with a strong tumor-enrichment PK profile and tumor-PD marker responses. Senexin C inhibits MV4-11 leukemia growth in a systemic in vivo model with good tolerability. |
| doi_str_mv | 10.1021/acs.jmedchem.1c01951 |
| format | Article |
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To improve their potency and metabolic stability, quinoline-based derivatives were designed through a structure-guided strategy based on the simulated drug–target docking model of Senexin A and Senexin B. A library of quinoline-Senexin derivatives was synthesized to explore the structure–activity relationship (SAR). An optimized compound 20a (Senexin C) exhibits potent CDK8/19 inhibitory activity with high selectivity. Senexin C is more metabolically stable and provides a more sustained inhibition of CDK8/19-dependent cellular gene expression when compared with the prototype inhibitor Senexin B. In vivo pharmacokinetic (PK) and pharmacodynamic (PD) evaluation using a novel tumor-based PD assay showed good oral bioavailability of Senexin C with a strong tumor-enrichment PK profile and tumor-PD marker responses. Senexin C inhibits MV4-11 leukemia growth in a systemic in vivo model with good tolerability.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.1c01951</identifier><identifier>PMID: 35114084</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Biological Availability ; Cell Line, Tumor ; Colonic Neoplasms - drug therapy ; Cyclin-Dependent Kinase 8 - antagonists & inhibitors ; Cyclin-Dependent Kinases - antagonists & inhibitors ; Humans ; Leukemia - drug therapy ; Mice ; Mice, Inbred BALB C ; Models, Molecular ; Molecular Docking Simulation ; Molecular Structure ; Protein Kinase Inhibitors - pharmacokinetics ; Protein Kinase Inhibitors - pharmacology ; Protein Kinase Inhibitors - toxicity ; Quinolines ; Structure-Activity Relationship ; Substrate Specificity ; Xenograft Model Antitumor Assays</subject><ispartof>Journal of medicinal chemistry, 2022-02, Vol.65 (4), p.3420-3433</ispartof><rights>2022 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a450t-3c9c0b794e995229e8e94beb62a3fcebe351462e02c16e498aa34658b824bc0c3</citedby><cites>FETCH-LOGICAL-a450t-3c9c0b794e995229e8e94beb62a3fcebe351462e02c16e498aa34658b824bc0c3</cites><orcidid>0000-0003-1706-9509 ; 0000-0002-5592-9082 ; 0000-0002-9211-1327</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.1c01951$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01951$$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/35114084$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Li</creatorcontrib><creatorcontrib>Cheng, Chen</creatorcontrib><creatorcontrib>Li, Jing</creatorcontrib><creatorcontrib>Wang, Lili</creatorcontrib><creatorcontrib>Chumanevich, Alexander A</creatorcontrib><creatorcontrib>Porter, Donald C</creatorcontrib><creatorcontrib>Mindich, Aleksei</creatorcontrib><creatorcontrib>Gorbunova, Svetlana</creatorcontrib><creatorcontrib>Roninson, Igor B</creatorcontrib><creatorcontrib>Chen, Mengqian</creatorcontrib><creatorcontrib>McInnes, Campbell</creatorcontrib><title>A Selective and Orally Bioavailable Quinoline-6-Carbonitrile-Based Inhibitor of CDK8/19 Mediator Kinase with Tumor-Enriched Pharmacokinetics</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Senexins are potent and selective quinazoline inhibitors of CDK8/19 Mediator kinases. To improve their potency and metabolic stability, quinoline-based derivatives were designed through a structure-guided strategy based on the simulated drug–target docking model of Senexin A and Senexin B. A library of quinoline-Senexin derivatives was synthesized to explore the structure–activity relationship (SAR). An optimized compound 20a (Senexin C) exhibits potent CDK8/19 inhibitory activity with high selectivity. Senexin C is more metabolically stable and provides a more sustained inhibition of CDK8/19-dependent cellular gene expression when compared with the prototype inhibitor Senexin B. In vivo pharmacokinetic (PK) and pharmacodynamic (PD) evaluation using a novel tumor-based PD assay showed good oral bioavailability of Senexin C with a strong tumor-enrichment PK profile and tumor-PD marker responses. Senexin C inhibits MV4-11 leukemia growth in a systemic in vivo model with good tolerability.</description><subject>Animals</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Biological Availability</subject><subject>Cell Line, Tumor</subject><subject>Colonic Neoplasms - drug therapy</subject><subject>Cyclin-Dependent Kinase 8 - antagonists & inhibitors</subject><subject>Cyclin-Dependent Kinases - antagonists & inhibitors</subject><subject>Humans</subject><subject>Leukemia - drug therapy</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Models, Molecular</subject><subject>Molecular Docking Simulation</subject><subject>Molecular Structure</subject><subject>Protein Kinase Inhibitors - pharmacokinetics</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Kinase Inhibitors - toxicity</subject><subject>Quinolines</subject><subject>Structure-Activity Relationship</subject><subject>Substrate Specificity</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kd1u1DAQhS0EokvhDRDyC3g7dpw0vkLtUqBqUUGUa2vszBKXxK6c7KK-Aw-Nl20ruOHK0vicMz8fY68lLCUoeYR-Wt6M1PmexqX0IE0tn7CFrBUI3YJ-yhYASgnVqOqAvZimGwCopKqes4OqllJDqxfs1wn_SgP5OWyJY-z4VcZhuOOnIeEWw4BuIP5lE2IaQiTRiBVml2KYcxhInOJEHT-PfXBhTpmnNV-9u2iPpOGfqAu4q12EWFT8Z5h7fr0ZUxZnMYcydcc_95hH9OlHiZ6Dn16yZ2scJnp1_x6yb-_PrlcfxeXVh_PVyaVAXcMsKm88uGOjyZhaKUMtGe3INQqrtSdHZT3dKALlZUPatIiVburWtUo7D746ZG_3ubcbt7sgxblsbW9zGDHf2YTB_vsTQ2-_p62VAFqp5rgk6H2Cz2maMq0fzRLsDo8teOwDHnuPp9je_N340fTAowhgL_hjT5scyx3-n_kbL4Wh5g</recordid><startdate>20220224</startdate><enddate>20220224</enddate><creator>Zhang, Li</creator><creator>Cheng, Chen</creator><creator>Li, Jing</creator><creator>Wang, Lili</creator><creator>Chumanevich, Alexander A</creator><creator>Porter, Donald C</creator><creator>Mindich, Aleksei</creator><creator>Gorbunova, Svetlana</creator><creator>Roninson, Igor B</creator><creator>Chen, Mengqian</creator><creator>McInnes, Campbell</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>5PM</scope><orcidid>https://orcid.org/0000-0003-1706-9509</orcidid><orcidid>https://orcid.org/0000-0002-5592-9082</orcidid><orcidid>https://orcid.org/0000-0002-9211-1327</orcidid></search><sort><creationdate>20220224</creationdate><title>A Selective and Orally Bioavailable Quinoline-6-Carbonitrile-Based Inhibitor of CDK8/19 Mediator Kinase with Tumor-Enriched Pharmacokinetics</title><author>Zhang, Li ; Cheng, Chen ; Li, Jing ; Wang, Lili ; Chumanevich, Alexander A ; Porter, Donald C ; Mindich, Aleksei ; Gorbunova, Svetlana ; Roninson, Igor B ; Chen, Mengqian ; McInnes, Campbell</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a450t-3c9c0b794e995229e8e94beb62a3fcebe351462e02c16e498aa34658b824bc0c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Biological Availability</topic><topic>Cell Line, Tumor</topic><topic>Colonic Neoplasms - drug therapy</topic><topic>Cyclin-Dependent Kinase 8 - antagonists & inhibitors</topic><topic>Cyclin-Dependent Kinases - antagonists & inhibitors</topic><topic>Humans</topic><topic>Leukemia - drug therapy</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Models, Molecular</topic><topic>Molecular Docking Simulation</topic><topic>Molecular Structure</topic><topic>Protein Kinase Inhibitors - pharmacokinetics</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Kinase Inhibitors - toxicity</topic><topic>Quinolines</topic><topic>Structure-Activity Relationship</topic><topic>Substrate Specificity</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Li</creatorcontrib><creatorcontrib>Cheng, Chen</creatorcontrib><creatorcontrib>Li, Jing</creatorcontrib><creatorcontrib>Wang, Lili</creatorcontrib><creatorcontrib>Chumanevich, Alexander A</creatorcontrib><creatorcontrib>Porter, Donald C</creatorcontrib><creatorcontrib>Mindich, Aleksei</creatorcontrib><creatorcontrib>Gorbunova, Svetlana</creatorcontrib><creatorcontrib>Roninson, Igor B</creatorcontrib><creatorcontrib>Chen, Mengqian</creatorcontrib><creatorcontrib>McInnes, Campbell</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Li</au><au>Cheng, Chen</au><au>Li, Jing</au><au>Wang, Lili</au><au>Chumanevich, Alexander A</au><au>Porter, Donald C</au><au>Mindich, Aleksei</au><au>Gorbunova, Svetlana</au><au>Roninson, Igor B</au><au>Chen, Mengqian</au><au>McInnes, Campbell</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Selective and Orally Bioavailable Quinoline-6-Carbonitrile-Based Inhibitor of CDK8/19 Mediator Kinase with Tumor-Enriched Pharmacokinetics</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2022-02-24</date><risdate>2022</risdate><volume>65</volume><issue>4</issue><spage>3420</spage><epage>3433</epage><pages>3420-3433</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Senexins are potent and selective quinazoline inhibitors of CDK8/19 Mediator kinases. To improve their potency and metabolic stability, quinoline-based derivatives were designed through a structure-guided strategy based on the simulated drug–target docking model of Senexin A and Senexin B. A library of quinoline-Senexin derivatives was synthesized to explore the structure–activity relationship (SAR). An optimized compound 20a (Senexin C) exhibits potent CDK8/19 inhibitory activity with high selectivity. Senexin C is more metabolically stable and provides a more sustained inhibition of CDK8/19-dependent cellular gene expression when compared with the prototype inhibitor Senexin B. In vivo pharmacokinetic (PK) and pharmacodynamic (PD) evaluation using a novel tumor-based PD assay showed good oral bioavailability of Senexin C with a strong tumor-enrichment PK profile and tumor-PD marker responses. Senexin C inhibits MV4-11 leukemia growth in a systemic in vivo model with good tolerability.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>35114084</pmid><doi>10.1021/acs.jmedchem.1c01951</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-1706-9509</orcidid><orcidid>https://orcid.org/0000-0002-5592-9082</orcidid><orcidid>https://orcid.org/0000-0002-9211-1327</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2022-02, Vol.65 (4), p.3420-3433 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | ACS Publications; MEDLINE |
| subjects | Animals Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Biological Availability Cell Line, Tumor Colonic Neoplasms - drug therapy Cyclin-Dependent Kinase 8 - antagonists & inhibitors Cyclin-Dependent Kinases - antagonists & inhibitors Humans Leukemia - drug therapy Mice Mice, Inbred BALB C Models, Molecular Molecular Docking Simulation Molecular Structure Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - toxicity Quinolines Structure-Activity Relationship Substrate Specificity Xenograft Model Antitumor Assays |
| title | A Selective and Orally Bioavailable Quinoline-6-Carbonitrile-Based Inhibitor of CDK8/19 Mediator Kinase with Tumor-Enriched Pharmacokinetics |
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