Discovery of heterocyclic ureas as a new class of raf kinase inhibitors: identification of a second generation lead by a combinatorial chemistry approach
Heterocyclic ureas, such as N-3-thienyl N′-aryl ureas, have been identified as novel inhibitors of raf kinase, a key mediator in the ras signal transduction pathway. Structure–activity relationships were established, and the potency of the screening hit was improved 10-fold to IC 50=1.7 μM. A combin...
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| Published in: | Bioorganic & medicinal chemistry letters Vol. 11; no. 20; pp. 2775 - 2778 |
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| Main Authors: | , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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22-10-2001
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| Abstract | Heterocyclic ureas, such as
N-3-thienyl
N′-aryl ureas, have been identified as novel inhibitors of raf kinase, a key mediator in the ras signal transduction pathway. Structure–activity relationships were established, and the potency of the screening hit was improved 10-fold to IC
50=1.7
μM. A combinatorial synthesis approach enabled the identification of a breakthrough lead (IC
50=0.54
μM) for a second generation series of heterocyclic urea raf kinase inhibitors.
Heterocyclic ureas have been identified as novel inhibitors of raf kinase, and structure–activity relationships were established. The potency of the screening hit was improved 10-fold to IC
50=1.7
μM, whereas a combinatorial synthesis approach enabled the identification of a breakthrough lead (IC
50=0.54 μM) for a second generation series of inhibitors. |
|---|---|
| AbstractList | Heterocyclic ureas, such as
N-3-thienyl
N′-aryl ureas, have been identified as novel inhibitors of raf kinase, a key mediator in the ras signal transduction pathway. Structure–activity relationships were established, and the potency of the screening hit was improved 10-fold to IC
50=1.7
μM. A combinatorial synthesis approach enabled the identification of a breakthrough lead (IC
50=0.54
μM) for a second generation series of heterocyclic urea raf kinase inhibitors.
Heterocyclic ureas have been identified as novel inhibitors of raf kinase, and structure–activity relationships were established. The potency of the screening hit was improved 10-fold to IC
50=1.7
μM, whereas a combinatorial synthesis approach enabled the identification of a breakthrough lead (IC
50=0.54 μM) for a second generation series of inhibitors. Heterocyclic ureas, such as N-3-thienyl N'-aryl ureas, have been identified as novel inhibitors of raf kinase, a key mediator in the ras signal transduction pathway. Structure-activity relationships were established, and the potency of the screening hit was improved 10-fold to IC(50)=1.7 microM. A combinatorial synthesis approach enabled the identification of a breakthrough lead (IC(50)=0.54 microM) for a second generation series of heterocyclic urea raf kinase inhibitors. |
| Author | Kennure, Nancy Lowinger, Timothy B Blum, Cheri L Wild, Hanno Marsh, Vivienne Kingery-Wood, Jill Caringal, Yolanda V Dally, Robert Rogers, Daniel H Katz, Michael E Smith, Roger A Barbosa, James Swartz, Stephen Lyons, John Walling, Tracy Johnson, Jeffrey S Bobko, Mark A Lee, Wendy |
| Author_xml | – sequence: 1 givenname: Roger A surname: Smith fullname: Smith, Roger A email: roger.smith.b@bayer.com organization: Department of Chemistry Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA – sequence: 2 givenname: James surname: Barbosa fullname: Barbosa, James organization: Department of Cancer Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA – sequence: 3 givenname: Cheri L surname: Blum fullname: Blum, Cheri L organization: Onyx Pharmaceuticals, 3031 Research Drive, Richmond, CA 94806, USA – sequence: 4 givenname: Mark A surname: Bobko fullname: Bobko, Mark A organization: Department of Chemistry Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA – sequence: 5 givenname: Yolanda V surname: Caringal fullname: Caringal, Yolanda V organization: Department of Chemistry Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA – sequence: 6 givenname: Robert surname: Dally fullname: Dally, Robert organization: Department of Chemistry Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA – sequence: 7 givenname: Jeffrey S surname: Johnson fullname: Johnson, Jeffrey S organization: Department of Chemistry Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA – sequence: 8 givenname: Michael E surname: Katz fullname: Katz, Michael E organization: Department of Cancer Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA – sequence: 9 givenname: Nancy surname: Kennure fullname: Kennure, Nancy organization: Department of Cancer Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA – sequence: 10 givenname: Jill surname: Kingery-Wood fullname: Kingery-Wood, Jill organization: Department of Chemistry Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA – sequence: 11 givenname: Wendy surname: Lee fullname: Lee, Wendy organization: Department of Chemistry Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA – sequence: 12 givenname: Timothy B surname: Lowinger fullname: Lowinger, Timothy B organization: Department of Chemistry Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA – sequence: 13 givenname: John surname: Lyons fullname: Lyons, John organization: Onyx Pharmaceuticals, 3031 Research Drive, Richmond, CA 94806, USA – sequence: 14 givenname: Vivienne surname: Marsh fullname: Marsh, Vivienne organization: Onyx Pharmaceuticals, 3031 Research Drive, Richmond, CA 94806, USA – sequence: 15 givenname: Daniel H surname: Rogers fullname: Rogers, Daniel H organization: Onyx Pharmaceuticals, 3031 Research Drive, Richmond, CA 94806, USA – sequence: 16 givenname: Stephen surname: Swartz fullname: Swartz, Stephen organization: Department of Chemistry Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA – sequence: 17 givenname: Tracy surname: Walling fullname: Walling, Tracy organization: Department of Cancer Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA – sequence: 18 givenname: Hanno surname: Wild fullname: Wild, Hanno organization: Department of Chemistry Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA |
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| Cites_doi | 10.1016/S0960-894X(00)00272-9 10.1016/S0960-894X(99)00668-X 10.1128/MCB.13.11.6615 10.1016/S0960-894X(00)00574-6 10.1517/13543776.8.12.1749 10.1038/nm0696-668 10.1016/S0960-894X(01)00571-6 10.1007/978-3-642-60393-8_16 10.1016/S0960-894X(00)00270-5 10.1146/annurev.bi.62.070193.004223 10.1517/13543776.11.3.405 |
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| Keywords | Antineoplastic agent Automation Isoxazole derivatives Enzyme Transferases Combinatorial chemistry Enzyme inhibitor In vitro Signal transduction Structure activity relation Kinase Chemical compound library Benzenic compound Ureas Onc gene Chemical synthesis Oxygen nitrogen heterocycle |
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| References_xml | – volume: 49 start-page: 4682 year: 1989 ident: BIB2 publication-title: Cancer Res. contributor: fullname: Bos – volume: 13 start-page: 6615 year: 1993 ident: BIB16 publication-title: Mol. Cell Biol. contributor: fullname: McCormick – volume: 11 start-page: 9 year: 2001 ident: BIB7 publication-title: Bioorg. Med. Chem. Lett. contributor: fullname: Scott – ident: BIB13 – ident: BIB12 – volume: 143 start-page: 237 year: 1997 ident: BIB3 publication-title: Rec. Results Cancer Res. contributor: fullname: Rapp – ident: BIB17 – volume: 62 start-page: 851 year: 1993 ident: BIB1 publication-title: Annu. Rev. Biochem. contributor: fullname: Willumsen – volume: 2 start-page: 668 year: 1996 ident: BIB4 publication-title: Nature Med. contributor: fullname: Fabbro – ident: BIB14 – volume: 10 start-page: 223 year: 2000 ident: BIB5 publication-title: Bioorg. Med. Chem. Lett. contributor: fullname: Wood – volume: 10 start-page: 2047 year: 2000 ident: BIB10 publication-title: Bioorg. Med. Chem. Lett. contributor: fullname: Shrikhande – ident: BIB15 – volume: 126 start-page: 139849 year: 1997 ident: BIB9 article-title: PCT Intl. Appl. WO 96/40673 publication-title: Chem. Abstr. contributor: fullname: McMahon – volume: 11 start-page: 405 year: 2001 ident: BIB8 publication-title: Exp. Opin, Ther. Pat. contributor: fullname: Dumas – volume: 10 start-page: 2051 year: 2000 ident: 10.1016/S0960-894X(01)00571-6_BIB10_2 publication-title: Bioorg. Med. Chem. Lett. doi: 10.1016/S0960-894X(00)00272-9 contributor: fullname: Dumas – volume: 10 start-page: 223 year: 2000 ident: 10.1016/S0960-894X(01)00571-6_BIB5 publication-title: Bioorg. Med. Chem. Lett. doi: 10.1016/S0960-894X(99)00668-X contributor: fullname: Lackey – volume: 13 start-page: 6615 year: 1993 ident: 10.1016/S0960-894X(01)00571-6_BIB16 publication-title: Mol. Cell Biol. doi: 10.1128/MCB.13.11.6615 contributor: fullname: MacDonald – volume: 11 start-page: 9 year: 2001 ident: 10.1016/S0960-894X(01)00571-6_BIB7 publication-title: Bioorg. Med. Chem. Lett. doi: 10.1016/S0960-894X(00)00574-6 contributor: fullname: Redman – volume: 8 start-page: 1749 year: 1998 ident: 10.1016/S0960-894X(01)00571-6_BIB8_2 publication-title: Exp. Opin. Ther. Pat. doi: 10.1517/13543776.8.12.1749 – volume: 49 start-page: 4682 year: 1989 ident: 10.1016/S0960-894X(01)00571-6_BIB2 publication-title: Cancer Res. contributor: fullname: Bos – volume: 2 start-page: 668 year: 1996 ident: 10.1016/S0960-894X(01)00571-6_BIB4 publication-title: Nature Med. doi: 10.1038/nm0696-668 contributor: fullname: Monia – ident: 10.1016/S0960-894X(01)00571-6_BIB11 doi: 10.1016/S0960-894X(01)00571-6 – volume: 143 start-page: 237 year: 1997 ident: 10.1016/S0960-894X(01)00571-6_BIB3 publication-title: Rec. Results Cancer Res. doi: 10.1007/978-3-642-60393-8_16 contributor: fullname: Naumann – volume: 126 start-page: 139849 year: 1997 ident: 10.1016/S0960-894X(01)00571-6_BIB9 article-title: PCT Intl. Appl. WO 96/40673 publication-title: Chem. Abstr. contributor: fullname: Tang – ident: 10.1016/S0960-894X(01)00571-6_BIB6 – volume: 10 start-page: 2047 year: 2000 ident: 10.1016/S0960-894X(01)00571-6_BIB10_1 publication-title: Bioorg. Med. Chem. Lett. doi: 10.1016/S0960-894X(00)00270-5 contributor: fullname: Dumas – volume: 62 start-page: 851 year: 1993 ident: 10.1016/S0960-894X(01)00571-6_BIB1 publication-title: Annu. Rev. Biochem. doi: 10.1146/annurev.bi.62.070193.004223 contributor: fullname: Lowy – volume: 11 start-page: 405 year: 2001 ident: 10.1016/S0960-894X(01)00571-6_BIB8_1 publication-title: Exp. Opin, Ther. Pat. doi: 10.1517/13543776.11.3.405 contributor: fullname: Dumas |
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| Snippet | Heterocyclic ureas, such as
N-3-thienyl
N′-aryl ureas, have been identified as novel inhibitors of raf kinase, a key mediator in the ras signal transduction... Heterocyclic ureas, such as N-3-thienyl N'-aryl ureas, have been identified as novel inhibitors of raf kinase, a key mediator in the ras signal transduction... |
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| SubjectTerms | Antineoplastic agents Biological and medical sciences General aspects Medical sciences Pharmacology. Drug treatments Proto-Oncogene Proteins c-raf - antagonists & inhibitors Structure-Activity Relationship Urea - analogs & derivatives Urea - chemical synthesis Urea - chemistry Urea - pharmacology |
| Title | Discovery of heterocyclic ureas as a new class of raf kinase inhibitors: identification of a second generation lead by a combinatorial chemistry approach |
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