Discovery of the Irreversible Covalent FGFR Inhibitor 8‑(3-(4-Acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3‑d]pyrimidin-7(8H)‑one (PRN1371) for the Treatment of Solid Tumors
Aberrant signaling of the FGF/FGFR pathway occurs frequently in cancers and is an oncogenic driver in many solid tumors. Clinical validation of FGFR as a therapeutic target has been demonstrated in bladder, liver, lung, breast, and gastric cancers. Our goal was to develop an irreversible covalent in...
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| Veröffentlicht in: | Journal of medicinal chemistry 2017-08, Vol.60 (15), p.6516-6527 |
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| creator | Brameld, Ken A Owens, Timothy D Verner, Erik Venetsanakos, Eleni Bradshaw, J. Michael Phan, Vernon T Tam, Danny Leung, Kwan Shu, Jin LaStant, Jacob Loughhead, David G Ton, Tony Karr, Dane E Gerritsen, Mary E Goldstein, David M Funk, Jens Oliver |
| description | Aberrant signaling of the FGF/FGFR pathway occurs frequently in cancers and is an oncogenic driver in many solid tumors. Clinical validation of FGFR as a therapeutic target has been demonstrated in bladder, liver, lung, breast, and gastric cancers. Our goal was to develop an irreversible covalent inhibitor of FGFR1–4 for use in oncology indications. An irreversible covalent binding mechanism imparts many desirable pharmacological benefits including high potency, selectivity, and prolonged target inhibition. Herein we report the structure-based design, medicinal chemistry optimization, and unique ADME assays of our irreversible covalent drug discovery program which culminated in the discovery of compound 34 (PRN1371), a highly selective and potent FGFR1–4 inhibitor. |
| doi_str_mv | 10.1021/acs.jmedchem.7b00360 |
| format | Article |
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Michael ; Phan, Vernon T ; Tam, Danny ; Leung, Kwan ; Shu, Jin ; LaStant, Jacob ; Loughhead, David G ; Ton, Tony ; Karr, Dane E ; Gerritsen, Mary E ; Goldstein, David M ; Funk, Jens Oliver</creator><creatorcontrib>Brameld, Ken A ; Owens, Timothy D ; Verner, Erik ; Venetsanakos, Eleni ; Bradshaw, J. Michael ; Phan, Vernon T ; Tam, Danny ; Leung, Kwan ; Shu, Jin ; LaStant, Jacob ; Loughhead, David G ; Ton, Tony ; Karr, Dane E ; Gerritsen, Mary E ; Goldstein, David M ; Funk, Jens Oliver</creatorcontrib><description>Aberrant signaling of the FGF/FGFR pathway occurs frequently in cancers and is an oncogenic driver in many solid tumors. Clinical validation of FGFR as a therapeutic target has been demonstrated in bladder, liver, lung, breast, and gastric cancers. Our goal was to develop an irreversible covalent inhibitor of FGFR1–4 for use in oncology indications. An irreversible covalent binding mechanism imparts many desirable pharmacological benefits including high potency, selectivity, and prolonged target inhibition. 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Michael</creatorcontrib><creatorcontrib>Phan, Vernon T</creatorcontrib><creatorcontrib>Tam, Danny</creatorcontrib><creatorcontrib>Leung, Kwan</creatorcontrib><creatorcontrib>Shu, Jin</creatorcontrib><creatorcontrib>LaStant, Jacob</creatorcontrib><creatorcontrib>Loughhead, David G</creatorcontrib><creatorcontrib>Ton, Tony</creatorcontrib><creatorcontrib>Karr, Dane E</creatorcontrib><creatorcontrib>Gerritsen, Mary E</creatorcontrib><creatorcontrib>Goldstein, David M</creatorcontrib><creatorcontrib>Funk, Jens Oliver</creatorcontrib><title>Discovery of the Irreversible Covalent FGFR Inhibitor 8‑(3-(4-Acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3‑d]pyrimidin-7(8H)‑one (PRN1371) for the Treatment of Solid Tumors</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Aberrant signaling of the FGF/FGFR pathway occurs frequently in cancers and is an oncogenic driver in many solid tumors. Clinical validation of FGFR as a therapeutic target has been demonstrated in bladder, liver, lung, breast, and gastric cancers. Our goal was to develop an irreversible covalent inhibitor of FGFR1–4 for use in oncology indications. An irreversible covalent binding mechanism imparts many desirable pharmacological benefits including high potency, selectivity, and prolonged target inhibition. Herein we report the structure-based design, medicinal chemistry optimization, and unique ADME assays of our irreversible covalent drug discovery program which culminated in the discovery of compound 34 (PRN1371), a highly selective and potent FGFR1–4 inhibitor.</description><subject>Animals</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Dogs</subject><subject>Drug Design</subject><subject>Drug Stability</subject><subject>Female</subject><subject>Humans</subject><subject>Intestinal Absorption</subject><subject>Macaca fascicularis</subject><subject>Male</subject><subject>Neoplasms - drug therapy</subject><subject>Pyridones - administration & dosage</subject><subject>Pyridones - chemical synthesis</subject><subject>Pyridones - pharmacokinetics</subject><subject>Pyridones - pharmacology</subject><subject>Pyrimidines - administration & dosage</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - pharmacokinetics</subject><subject>Pyrimidines - pharmacology</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptor, Fibroblast Growth Factor, Type 1 - antagonists & inhibitors</subject><subject>Receptor, Fibroblast Growth Factor, Type 2 - antagonists & inhibitors</subject><subject>Receptor, Fibroblast Growth Factor, Type 3 - antagonists & inhibitors</subject><subject>Receptor, Fibroblast Growth Factor, Type 4 - antagonists & inhibitors</subject><subject>Receptors, Fibroblast Growth Factor - antagonists & inhibitors</subject><subject>Solubility</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UUuO1DAQjRCIaQZugFCWaand-JM4yXLUQ8-0NAI09A6hyHaqFY-cONjJiLDiChyES3AUdtwCh-5hyapU5Vev3vOLopcErwmm5LVQfn3XQq0aaNe5xJhx_ChakIxilBY4fRwtMKYUUU7ZWfTM-zscMISyp9EZLTjPCC0W0e9L7ZW9BzfF9hAPDcQ75yD0XksD8cbeCwPdEG-vtrfxrmu01IN1cfHr2_eEoSRFF8pNxk7m549e9-DEV90hgiaz7J3tQ0EcJXTFUa1VY6yziK2y0LQwNPbL1DfQzSCKknkyGdHqzi4D2eR0bT_SFQuX6k_HQavrwJ4nxfUyTG0HcfL-9i1hOVnGh6Bqlr93IIZ2lhz8fLBG1_F-bK3zz6MnB2E8vDjV82i_fbPfXKObd1e7zcUNEqxMBwTywJQEJRQoyTkjuRQFZKrktcqkpJBywrFUkEkqc6wgLRWnpchKRuu8YOdRcqQN_j-P4IeqDT8MxogO7OgrUpKMpVlWpgGaHqHKWe8dHKo-eBRuqgiu5oyrkHH1kHF1yjisvTpdGGV4-7f0EGoA4CPg77odXRf8_p_zD4RGvMo</recordid><startdate>20170810</startdate><enddate>20170810</enddate><creator>Brameld, Ken A</creator><creator>Owens, Timothy D</creator><creator>Verner, Erik</creator><creator>Venetsanakos, Eleni</creator><creator>Bradshaw, J. 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Michael ; Phan, Vernon T ; Tam, Danny ; Leung, Kwan ; Shu, Jin ; LaStant, Jacob ; Loughhead, David G ; Ton, Tony ; Karr, Dane E ; Gerritsen, Mary E ; Goldstein, David M ; Funk, Jens Oliver</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a394t-ebf3cbecacecb66317ba8e5c96dc5bb2e46160bce5b2b70ce49c629a5932d783</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Dogs</topic><topic>Drug Design</topic><topic>Drug Stability</topic><topic>Female</topic><topic>Humans</topic><topic>Intestinal Absorption</topic><topic>Macaca fascicularis</topic><topic>Male</topic><topic>Neoplasms - drug therapy</topic><topic>Pyridones - administration & dosage</topic><topic>Pyridones - chemical synthesis</topic><topic>Pyridones - pharmacokinetics</topic><topic>Pyridones - pharmacology</topic><topic>Pyrimidines - administration & dosage</topic><topic>Pyrimidines - chemical synthesis</topic><topic>Pyrimidines - pharmacokinetics</topic><topic>Pyrimidines - pharmacology</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptor, Fibroblast Growth Factor, Type 1 - antagonists & inhibitors</topic><topic>Receptor, Fibroblast Growth Factor, Type 2 - antagonists & inhibitors</topic><topic>Receptor, Fibroblast Growth Factor, Type 3 - antagonists & inhibitors</topic><topic>Receptor, Fibroblast Growth Factor, Type 4 - antagonists & inhibitors</topic><topic>Receptors, Fibroblast Growth Factor - antagonists & inhibitors</topic><topic>Solubility</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Brameld, Ken A</creatorcontrib><creatorcontrib>Owens, Timothy D</creatorcontrib><creatorcontrib>Verner, Erik</creatorcontrib><creatorcontrib>Venetsanakos, Eleni</creatorcontrib><creatorcontrib>Bradshaw, J. 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Michael</au><au>Phan, Vernon T</au><au>Tam, Danny</au><au>Leung, Kwan</au><au>Shu, Jin</au><au>LaStant, Jacob</au><au>Loughhead, David G</au><au>Ton, Tony</au><au>Karr, Dane E</au><au>Gerritsen, Mary E</au><au>Goldstein, David M</au><au>Funk, Jens Oliver</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of the Irreversible Covalent FGFR Inhibitor 8‑(3-(4-Acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3‑d]pyrimidin-7(8H)‑one (PRN1371) for the Treatment of Solid Tumors</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2017-08-10</date><risdate>2017</risdate><volume>60</volume><issue>15</issue><spage>6516</spage><epage>6527</epage><pages>6516-6527</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Aberrant signaling of the FGF/FGFR pathway occurs frequently in cancers and is an oncogenic driver in many solid tumors. Clinical validation of FGFR as a therapeutic target has been demonstrated in bladder, liver, lung, breast, and gastric cancers. Our goal was to develop an irreversible covalent inhibitor of FGFR1–4 for use in oncology indications. An irreversible covalent binding mechanism imparts many desirable pharmacological benefits including high potency, selectivity, and prolonged target inhibition. Herein we report the structure-based design, medicinal chemistry optimization, and unique ADME assays of our irreversible covalent drug discovery program which culminated in the discovery of compound 34 (PRN1371), a highly selective and potent FGFR1–4 inhibitor.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>28665128</pmid><doi>10.1021/acs.jmedchem.7b00360</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-8643-3218</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2017-08, Vol.60 (15), p.6516-6527 |
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| subjects | Animals Antineoplastic Agents - administration & dosage Antineoplastic Agents - chemical synthesis Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Cell Line, Tumor Dogs Drug Design Drug Stability Female Humans Intestinal Absorption Macaca fascicularis Male Neoplasms - drug therapy Pyridones - administration & dosage Pyridones - chemical synthesis Pyridones - pharmacokinetics Pyridones - pharmacology Pyrimidines - administration & dosage Pyrimidines - chemical synthesis Pyrimidines - pharmacokinetics Pyrimidines - pharmacology Rats, Sprague-Dawley Receptor, Fibroblast Growth Factor, Type 1 - antagonists & inhibitors Receptor, Fibroblast Growth Factor, Type 2 - antagonists & inhibitors Receptor, Fibroblast Growth Factor, Type 3 - antagonists & inhibitors Receptor, Fibroblast Growth Factor, Type 4 - antagonists & inhibitors Receptors, Fibroblast Growth Factor - antagonists & inhibitors Solubility Structure-Activity Relationship |
| title | Discovery of the Irreversible Covalent FGFR Inhibitor 8‑(3-(4-Acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3‑d]pyrimidin-7(8H)‑one (PRN1371) for the Treatment of Solid Tumors |
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