Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations
Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M ga...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 2014-06, Vol.57 (11), p.4720-4744 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 4744 |
|---|---|
| container_issue | 11 |
| container_start_page | 4720 |
| container_title | Journal of medicinal chemistry |
| container_volume | 57 |
| creator | Johnson, Ted W Richardson, Paul F Bailey, Simon Brooun, Alexei Burke, Benjamin J Collins, Michael R Cui, J Jean Deal, Judith G Deng, Ya-Li Dinh, Dac Engstrom, Lars D He, Mingying Hoffman, Jacqui Hoffman, Robert L Huang, Qinhua Kania, Robert S Kath, John C Lam, Hieu Lam, Justine L Le, Phuong T Lingardo, Laura Liu, Wei McTigue, Michele Palmer, Cynthia L Sach, Neal W Smeal, Tod Smith, Graham L Stewart, Albert E Timofeevski, Sergei Zhu, Huichun Zhu, Jinjiang Zou, Helen Y Edwards, Martin P |
| description | Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity. |
| doi_str_mv | 10.1021/jm500261q |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_osti_</sourceid><recordid>TN_cdi_osti_scitechconnect_1405011</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1535626842</sourcerecordid><originalsourceid>FETCH-LOGICAL-c312t-daefb0eabce35c583e4e139401442d2d9f76c412652c90690a0cf928744ae13d3</originalsourceid><addsrcrecordid>eNo9kkFv1DAQhQMC0aVw4A8gq6ddKQbbcbKbY1UoRaxUVOBUVdHEmTQuiZ3aDmz66_G2pSdLz9-8GY9fkrzj7ANngn-8GXLGRMFvnycLngtG5YbJF8kiioKKQmQHyWvvbxhjGRfZq-RAyA0vOS8Wz24-aa_sH3QzsS1ZcnaxomsKgzaWckHbfrLOUpFylvKCBqcHDN3cU55Tu4tIlPN4k_I1DRgcdHOz58_oJpV0uYfR2NU4O7izvb2UaUa7q0uRxiJ-RWs0d3YHjYY7ULPq7b1Hg0obpBlV4GprdOzaI1l-P6WskEVWCrFKCZABlLP7Kq2INp2udbBu_wowMPbgQ9T7eRg7OwD5rQ34aHK8_baKQEMUddYTa5S9RoOEk-XF-Q--In916MjoMNoaraAntQNtCO5G6yeH97W1s9BQP6IKbhrIGMc2aiZwHUkfSOxBHXrtA5hAhilA0Nb4N8nLFnqPbx_Pw-TX6eefJ2d0e_7l68nxlqr4O4E2gG3NEGqFWa7yTYYSeVZKxqUUjWjKdl0oyUWRC1WyomTAVFuKzVpKiGCTHSZHD742rqDySgdUnbLGxHErLlnOOI_Q8gEanb2d0IdqiEHAvgeDdvIVz7O8EMVGioiuHtC4bu8dttUYYwBurjir9vmrnvIX2fePtlM9YPNE_g9c9g9NMdRS</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1535626842</pqid></control><display><type>article</type><title>Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations</title><source>ACS Publications</source><source>MEDLINE</source><creator>Johnson, Ted W ; Richardson, Paul F ; Bailey, Simon ; Brooun, Alexei ; Burke, Benjamin J ; Collins, Michael R ; Cui, J Jean ; Deal, Judith G ; Deng, Ya-Li ; Dinh, Dac ; Engstrom, Lars D ; He, Mingying ; Hoffman, Jacqui ; Hoffman, Robert L ; Huang, Qinhua ; Kania, Robert S ; Kath, John C ; Lam, Hieu ; Lam, Justine L ; Le, Phuong T ; Lingardo, Laura ; Liu, Wei ; McTigue, Michele ; Palmer, Cynthia L ; Sach, Neal W ; Smeal, Tod ; Smith, Graham L ; Stewart, Albert E ; Timofeevski, Sergei ; Zhu, Huichun ; Zhu, Jinjiang ; Zou, Helen Y ; Edwards, Martin P</creator><creatorcontrib>Johnson, Ted W ; Richardson, Paul F ; Bailey, Simon ; Brooun, Alexei ; Burke, Benjamin J ; Collins, Michael R ; Cui, J Jean ; Deal, Judith G ; Deng, Ya-Li ; Dinh, Dac ; Engstrom, Lars D ; He, Mingying ; Hoffman, Jacqui ; Hoffman, Robert L ; Huang, Qinhua ; Kania, Robert S ; Kath, John C ; Lam, Hieu ; Lam, Justine L ; Le, Phuong T ; Lingardo, Laura ; Liu, Wei ; McTigue, Michele ; Palmer, Cynthia L ; Sach, Neal W ; Smeal, Tod ; Smith, Graham L ; Stewart, Albert E ; Timofeevski, Sergei ; Zhu, Huichun ; Zhu, Jinjiang ; Zou, Helen Y ; Edwards, Martin P ; Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><description>Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm500261q</identifier><identifier>PMID: 24819116</identifier><language>eng</language><publisher>United States: American Chemical Society (ACS)</publisher><subject>60 APPLIED LIFE SCIENCES ; Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - pharmacology ; Brain - metabolism ; Crystallography, X-Ray ; Drug Resistance, Neoplasm ; Humans ; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY ; Lactams, Macrocyclic - chemical synthesis ; Lactams, Macrocyclic - pharmacokinetics ; Lactams, Macrocyclic - pharmacology ; Mice ; Microsomes, Liver - metabolism ; Models, Molecular ; Mutation ; NIH 3T3 Cells ; Protein-Tyrosine Kinases - antagonists & inhibitors ; Proto-Oncogene Proteins - antagonists & inhibitors ; Rats ; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors ; Receptor Protein-Tyrosine Kinases - genetics ; Stereoisomerism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2014-06, Vol.57 (11), p.4720-4744</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c312t-daefb0eabce35c583e4e139401442d2d9f76c412652c90690a0cf928744ae13d3</citedby><cites>FETCH-LOGICAL-c312t-daefb0eabce35c583e4e139401442d2d9f76c412652c90690a0cf928744ae13d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,2752,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24819116$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1405011$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Johnson, Ted W</creatorcontrib><creatorcontrib>Richardson, Paul F</creatorcontrib><creatorcontrib>Bailey, Simon</creatorcontrib><creatorcontrib>Brooun, Alexei</creatorcontrib><creatorcontrib>Burke, Benjamin J</creatorcontrib><creatorcontrib>Collins, Michael R</creatorcontrib><creatorcontrib>Cui, J Jean</creatorcontrib><creatorcontrib>Deal, Judith G</creatorcontrib><creatorcontrib>Deng, Ya-Li</creatorcontrib><creatorcontrib>Dinh, Dac</creatorcontrib><creatorcontrib>Engstrom, Lars D</creatorcontrib><creatorcontrib>He, Mingying</creatorcontrib><creatorcontrib>Hoffman, Jacqui</creatorcontrib><creatorcontrib>Hoffman, Robert L</creatorcontrib><creatorcontrib>Huang, Qinhua</creatorcontrib><creatorcontrib>Kania, Robert S</creatorcontrib><creatorcontrib>Kath, John C</creatorcontrib><creatorcontrib>Lam, Hieu</creatorcontrib><creatorcontrib>Lam, Justine L</creatorcontrib><creatorcontrib>Le, Phuong T</creatorcontrib><creatorcontrib>Lingardo, Laura</creatorcontrib><creatorcontrib>Liu, Wei</creatorcontrib><creatorcontrib>McTigue, Michele</creatorcontrib><creatorcontrib>Palmer, Cynthia L</creatorcontrib><creatorcontrib>Sach, Neal W</creatorcontrib><creatorcontrib>Smeal, Tod</creatorcontrib><creatorcontrib>Smith, Graham L</creatorcontrib><creatorcontrib>Stewart, Albert E</creatorcontrib><creatorcontrib>Timofeevski, Sergei</creatorcontrib><creatorcontrib>Zhu, Huichun</creatorcontrib><creatorcontrib>Zhu, Jinjiang</creatorcontrib><creatorcontrib>Zou, Helen Y</creatorcontrib><creatorcontrib>Edwards, Martin P</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations</title><title>Journal of medicinal chemistry</title><addtitle>J Med Chem</addtitle><description>Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>Animals</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Brain - metabolism</subject><subject>Crystallography, X-Ray</subject><subject>Drug Resistance, Neoplasm</subject><subject>Humans</subject><subject>INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY</subject><subject>Lactams, Macrocyclic - chemical synthesis</subject><subject>Lactams, Macrocyclic - pharmacokinetics</subject><subject>Lactams, Macrocyclic - pharmacology</subject><subject>Mice</subject><subject>Microsomes, Liver - metabolism</subject><subject>Models, Molecular</subject><subject>Mutation</subject><subject>NIH 3T3 Cells</subject><subject>Protein-Tyrosine Kinases - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins - antagonists & inhibitors</subject><subject>Rats</subject><subject>Receptor Protein-Tyrosine Kinases - antagonists & inhibitors</subject><subject>Receptor Protein-Tyrosine Kinases - genetics</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kkFv1DAQhQMC0aVw4A8gq6ddKQbbcbKbY1UoRaxUVOBUVdHEmTQuiZ3aDmz66_G2pSdLz9-8GY9fkrzj7ANngn-8GXLGRMFvnycLngtG5YbJF8kiioKKQmQHyWvvbxhjGRfZq-RAyA0vOS8Wz24-aa_sH3QzsS1ZcnaxomsKgzaWckHbfrLOUpFylvKCBqcHDN3cU55Tu4tIlPN4k_I1DRgcdHOz58_oJpV0uYfR2NU4O7izvb2UaUa7q0uRxiJ-RWs0d3YHjYY7ULPq7b1Hg0obpBlV4GprdOzaI1l-P6WskEVWCrFKCZABlLP7Kq2INp2udbBu_wowMPbgQ9T7eRg7OwD5rQ34aHK8_baKQEMUddYTa5S9RoOEk-XF-Q--In916MjoMNoaraAntQNtCO5G6yeH97W1s9BQP6IKbhrIGMc2aiZwHUkfSOxBHXrtA5hAhilA0Nb4N8nLFnqPbx_Pw-TX6eefJ2d0e_7l68nxlqr4O4E2gG3NEGqFWa7yTYYSeVZKxqUUjWjKdl0oyUWRC1WyomTAVFuKzVpKiGCTHSZHD742rqDySgdUnbLGxHErLlnOOI_Q8gEanb2d0IdqiEHAvgeDdvIVz7O8EMVGioiuHtC4bu8dttUYYwBurjir9vmrnvIX2fePtlM9YPNE_g9c9g9NMdRS</recordid><startdate>20140612</startdate><enddate>20140612</enddate><creator>Johnson, Ted W</creator><creator>Richardson, Paul F</creator><creator>Bailey, Simon</creator><creator>Brooun, Alexei</creator><creator>Burke, Benjamin J</creator><creator>Collins, Michael R</creator><creator>Cui, J Jean</creator><creator>Deal, Judith G</creator><creator>Deng, Ya-Li</creator><creator>Dinh, Dac</creator><creator>Engstrom, Lars D</creator><creator>He, Mingying</creator><creator>Hoffman, Jacqui</creator><creator>Hoffman, Robert L</creator><creator>Huang, Qinhua</creator><creator>Kania, Robert S</creator><creator>Kath, John C</creator><creator>Lam, Hieu</creator><creator>Lam, Justine L</creator><creator>Le, Phuong T</creator><creator>Lingardo, Laura</creator><creator>Liu, Wei</creator><creator>McTigue, Michele</creator><creator>Palmer, Cynthia L</creator><creator>Sach, Neal W</creator><creator>Smeal, Tod</creator><creator>Smith, Graham L</creator><creator>Stewart, Albert E</creator><creator>Timofeevski, Sergei</creator><creator>Zhu, Huichun</creator><creator>Zhu, Jinjiang</creator><creator>Zou, Helen Y</creator><creator>Edwards, Martin P</creator><general>American Chemical Society (ACS)</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>OTOTI</scope></search><sort><creationdate>20140612</creationdate><title>Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations</title><author>Johnson, Ted W ; Richardson, Paul F ; Bailey, Simon ; Brooun, Alexei ; Burke, Benjamin J ; Collins, Michael R ; Cui, J Jean ; Deal, Judith G ; Deng, Ya-Li ; Dinh, Dac ; Engstrom, Lars D ; He, Mingying ; Hoffman, Jacqui ; Hoffman, Robert L ; Huang, Qinhua ; Kania, Robert S ; Kath, John C ; Lam, Hieu ; Lam, Justine L ; Le, Phuong T ; Lingardo, Laura ; Liu, Wei ; McTigue, Michele ; Palmer, Cynthia L ; Sach, Neal W ; Smeal, Tod ; Smith, Graham L ; Stewart, Albert E ; Timofeevski, Sergei ; Zhu, Huichun ; Zhu, Jinjiang ; Zou, Helen Y ; Edwards, Martin P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c312t-daefb0eabce35c583e4e139401442d2d9f76c412652c90690a0cf928744ae13d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>Animals</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Brain - metabolism</topic><topic>Crystallography, X-Ray</topic><topic>Drug Resistance, Neoplasm</topic><topic>Humans</topic><topic>INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY</topic><topic>Lactams, Macrocyclic - chemical synthesis</topic><topic>Lactams, Macrocyclic - pharmacokinetics</topic><topic>Lactams, Macrocyclic - pharmacology</topic><topic>Mice</topic><topic>Microsomes, Liver - metabolism</topic><topic>Models, Molecular</topic><topic>Mutation</topic><topic>NIH 3T3 Cells</topic><topic>Protein-Tyrosine Kinases - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins - antagonists & inhibitors</topic><topic>Rats</topic><topic>Receptor Protein-Tyrosine Kinases - antagonists & inhibitors</topic><topic>Receptor Protein-Tyrosine Kinases - genetics</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Johnson, Ted W</creatorcontrib><creatorcontrib>Richardson, Paul F</creatorcontrib><creatorcontrib>Bailey, Simon</creatorcontrib><creatorcontrib>Brooun, Alexei</creatorcontrib><creatorcontrib>Burke, Benjamin J</creatorcontrib><creatorcontrib>Collins, Michael R</creatorcontrib><creatorcontrib>Cui, J Jean</creatorcontrib><creatorcontrib>Deal, Judith G</creatorcontrib><creatorcontrib>Deng, Ya-Li</creatorcontrib><creatorcontrib>Dinh, Dac</creatorcontrib><creatorcontrib>Engstrom, Lars D</creatorcontrib><creatorcontrib>He, Mingying</creatorcontrib><creatorcontrib>Hoffman, Jacqui</creatorcontrib><creatorcontrib>Hoffman, Robert L</creatorcontrib><creatorcontrib>Huang, Qinhua</creatorcontrib><creatorcontrib>Kania, Robert S</creatorcontrib><creatorcontrib>Kath, John C</creatorcontrib><creatorcontrib>Lam, Hieu</creatorcontrib><creatorcontrib>Lam, Justine L</creatorcontrib><creatorcontrib>Le, Phuong T</creatorcontrib><creatorcontrib>Lingardo, Laura</creatorcontrib><creatorcontrib>Liu, Wei</creatorcontrib><creatorcontrib>McTigue, Michele</creatorcontrib><creatorcontrib>Palmer, Cynthia L</creatorcontrib><creatorcontrib>Sach, Neal W</creatorcontrib><creatorcontrib>Smeal, Tod</creatorcontrib><creatorcontrib>Smith, Graham L</creatorcontrib><creatorcontrib>Stewart, Albert E</creatorcontrib><creatorcontrib>Timofeevski, Sergei</creatorcontrib><creatorcontrib>Zhu, Huichun</creatorcontrib><creatorcontrib>Zhu, Jinjiang</creatorcontrib><creatorcontrib>Zou, Helen Y</creatorcontrib><creatorcontrib>Edwards, Martin P</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</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>OSTI.GOV</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Johnson, Ted W</au><au>Richardson, Paul F</au><au>Bailey, Simon</au><au>Brooun, Alexei</au><au>Burke, Benjamin J</au><au>Collins, Michael R</au><au>Cui, J Jean</au><au>Deal, Judith G</au><au>Deng, Ya-Li</au><au>Dinh, Dac</au><au>Engstrom, Lars D</au><au>He, Mingying</au><au>Hoffman, Jacqui</au><au>Hoffman, Robert L</au><au>Huang, Qinhua</au><au>Kania, Robert S</au><au>Kath, John C</au><au>Lam, Hieu</au><au>Lam, Justine L</au><au>Le, Phuong T</au><au>Lingardo, Laura</au><au>Liu, Wei</au><au>McTigue, Michele</au><au>Palmer, Cynthia L</au><au>Sach, Neal W</au><au>Smeal, Tod</au><au>Smith, Graham L</au><au>Stewart, Albert E</au><au>Timofeevski, Sergei</au><au>Zhu, Huichun</au><au>Zhu, Jinjiang</au><au>Zou, Helen Y</au><au>Edwards, Martin P</au><aucorp>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J Med Chem</addtitle><date>2014-06-12</date><risdate>2014</risdate><volume>57</volume><issue>11</issue><spage>4720</spage><epage>4744</epage><pages>4720-4744</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.</abstract><cop>United States</cop><pub>American Chemical Society (ACS)</pub><pmid>24819116</pmid><doi>10.1021/jm500261q</doi><tpages>25</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2014-06, Vol.57 (11), p.4720-4744 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_osti_scitechconnect_1405011 |
| source | ACS Publications; MEDLINE |
| subjects | 60 APPLIED LIFE SCIENCES Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Brain - metabolism Crystallography, X-Ray Drug Resistance, Neoplasm Humans INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY Lactams, Macrocyclic - chemical synthesis Lactams, Macrocyclic - pharmacokinetics Lactams, Macrocyclic - pharmacology Mice Microsomes, Liver - metabolism Models, Molecular Mutation NIH 3T3 Cells Protein-Tyrosine Kinases - antagonists & inhibitors Proto-Oncogene Proteins - antagonists & inhibitors Rats Receptor Protein-Tyrosine Kinases - antagonists & inhibitors Receptor Protein-Tyrosine Kinases - genetics Stereoisomerism Structure-Activity Relationship |
| title | Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-30T16%3A04%3A50IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_osti_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Discovery%20of%20(10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo%5B4,3-h%5D%5B2,5,11%5D-benzoxadiazacyclotetradecine-3-carbonitrile%20(PF-06463922),%20a%20macrocyclic%20inhibitor%20of%20anaplastic%20lymphoma%20kinase%20(ALK)%20and%20c-ros%20oncogene%201%20(ROS1)%20with%20preclinical%20brain%20exposure%20and%20broad-spectrum%20potency%20against%20ALK-resistant%20mutations&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Johnson,%20Ted%20W&rft.aucorp=Argonne%20National%20Lab.%20(ANL),%20Argonne,%20IL%20(United%20States).%20Advanced%20Photon%20Source%20(APS)&rft.date=2014-06-12&rft.volume=57&rft.issue=11&rft.spage=4720&rft.epage=4744&rft.pages=4720-4744&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/jm500261q&rft_dat=%3Cproquest_osti_%3E1535626842%3C/proquest_osti_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1535626842&rft_id=info:pmid/24819116&rfr_iscdi=true |