Discovery and synthesis of N2,N4-substitued-cycloalkyl[d]pyrimidine 2,4-diamine analogs： The first examples of small-molecular FGFR-1 activator
A series of novel, cycloalkyl-modified pazopanib analogs 2 and 3 were designed and synthesized. Their kinase modulatory effects on FGFR-1, VEGFR-2, PDGFR-β and c-KIT were evaluated by the caliper mobility shift assay. Introduction of cycloalkyl into the pyrimidine linker of pazopanib almost abolishe...
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| Published in | Chinese chemical letters Vol. 25; no. 7; pp. 989 - 994 |
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| Main Authors | , , , , , |
| Format | Journal Article |
| Language | English |
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Elsevier B.V
01.07.2014
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| Abstract | A series of novel, cycloalkyl-modified pazopanib analogs 2 and 3 were designed and synthesized. Their kinase modulatory effects on FGFR-1, VEGFR-2, PDGFR-β and c-KIT were evaluated by the caliper mobility shift assay. Introduction of cycloalkyl into the pyrimidine linker of pazopanib almost abolished the four kinases inhibitory potency of compounds 2 and 3, but surprisingly, resulted in good activation effects on FGFR-1. Compounds 3d and 3g showed double-digit, nanomolar, selective activation effects on FGFR-1, and could be classified as first-generation small molecular activators of FGFR-1 kinase. |
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| AbstractList | A series of novel, cycloalkyl-modified pazopanib analogs were designed and synthesized. Compounds 3d and 3g showed double-digit, nanomolar selective activation effects on FGFR-1, and could be classified as first-generation small molecular activators of FGFR-1 kinase.
A series of novel, cycloalkyl-modified pazopanib analogs 2 and 3 were designed and synthesized. Their kinase modulatory effects on FGFR-1, VEGFR-2, PDGFR-β, and c-KIT were evaluated by the caliper mobility shift assay. Introduction of cycloalkyl into the pyrimidine linker of pazopanib almost abolished the four kinases inhibitory potency of compounds 2 and 3, but surprisingly, resulted in good activation effects on FGFR-1. Compounds 3d and 3g showed double-digit, nanomolar, selective activation effects on FGFR-1, and could be classified as first-generation small molecular activators of FGFR-1 kinase. A series of novel, cycloalkyl-modified pazopanib analogs 2 and 3 were designed and synthesized. Their kinase modulatory effects on FGFR-1, VEGFR-2, PDGFR-β and c-KIT were evaluated by the caliper mobility shift assay. Introduction of cycloalkyl into the pyrimidine linker of pazopanib almost abolished the four kinases inhibitory potency of compounds 2 and 3, but surprisingly, resulted in good activation effects on FGFR-1. Compounds 3d and 3g showed double-digit, nanomolar, selective activation effects on FGFR-1, and could be classified as first-generation small molecular activators of FGFR-1 kinase. |
| Author | Bao-Li Li Fang Xiao Wen-Chao Lu Yu-Yun Sun Jin Zhu Jian Li |
| AuthorAffiliation | Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China Department of Pharmacy, The Second Hospital of Jilin University, Jilin 130041, China China Resources Double-Crane Pharmaceutical Co., Ltd., Beijing 100121, China |
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| Cites_doi | 10.1016/j.drudis.2013.07.021 10.1038/nrc2780 10.1016/j.ccr.2007.11.004 10.1182/blood-2007-01-067314 10.1016/S0065-230X(08)60821-0 10.1126/science.2544996 10.1016/j.cytogfr.2005.01.001 10.1016/j.bbamcr.2012.01.004 10.1021/jm800566m |
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| Keywords | Cycloalkyl[d]pyrimidine derivatives Chemical probe Activator FGFR-1 |
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| Notes | Cycloalkyl[d]pyrimidine derivatives;FGFR-1;Activator;Chemical probe 11-2710/O6 A series of novel, cycloalkyl-modified pazopanib analogs 2 and 3 were designed and synthesized. Their kinase modulatory effects on FGFR-1, VEGFR-2, PDGFR-β and c-KIT were evaluated by the caliper mobility shift assay. Introduction of cycloalkyl into the pyrimidine linker of pazopanib almost abolished the four kinases inhibitory potency of compounds 2 and 3, but surprisingly, resulted in good activation effects on FGFR-1. Compounds 3d and 3g showed double-digit, nanomolar, selective activation effects on FGFR-1, and could be classified as first-generation small molecular activators of FGFR-1 kinase. |
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| References | Eswarakumar, Lax, Schlessinger (bib0015) 2005; 16 Ahmad, Iwata, Leung (bib0025) 2012; 1823 Harris, Boloor, Cheung (bib0045) 2008; 51 Ho, Yeo, Kang, Chua (bib0030) 2014; 19 Acevedo, Gangula, Freeman (bib0035) 2007; 12 Johnson, Williams (bib0005) 1993; 60 Turner, Grose (bib0020) 2010; 10 Lee, Johnson, Cousens, Fried, Williams (bib0010) 1989; 245 Magnusson, Dimberg, Mellberg, Lukinius, Claesson-Welsh (bib0040) 2007; 110 Johnson (10.1016/j.cclet.2014.06.010_bib0005) 1993; 60 Lee (10.1016/j.cclet.2014.06.010_bib0010) 1989; 245 Turner (10.1016/j.cclet.2014.06.010_bib0020) 2010; 10 Harris (10.1016/j.cclet.2014.06.010_bib0045) 2008; 51 Ahmad (10.1016/j.cclet.2014.06.010_bib0025) 2012; 1823 Magnusson (10.1016/j.cclet.2014.06.010_bib0040) 2007; 110 Eswarakumar (10.1016/j.cclet.2014.06.010_bib0015) 2005; 16 Acevedo (10.1016/j.cclet.2014.06.010_bib0035) 2007; 12 Ho (10.1016/j.cclet.2014.06.010_bib0030) 2014; 19 |
| References_xml | – volume: 10 start-page: 116 year: 2010 end-page: 129 ident: bib0020 article-title: Fibroblast growth factor signalling: from development to cancer publication-title: Nat. Rev. Cancer – volume: 1823 start-page: 850 year: 2012 end-page: 860 ident: bib0025 article-title: Mechanisms of FGFR-mediated carcinogenesis publication-title: Biochim. Biophys. Acta – volume: 245 start-page: 57 year: 1989 end-page: 59 ident: bib0010 article-title: Purification and complementary DNA cloning of a receptor for basic fibroblast growth factor publication-title: Science – volume: 110 start-page: 4214 year: 2007 end-page: 4222 ident: bib0040 article-title: FGFR-1 regulates angiogenesis through cytokines interleukin-4 and pleiotrophin publication-title: Blood – volume: 60 start-page: 1 year: 1993 end-page: 41 ident: bib0005 article-title: Structural and functional diversity in the FGF receptor multigene family publication-title: Adv. Cancer Res. – volume: 16 start-page: 139 year: 2005 end-page: 149 ident: bib0015 article-title: Cellular signaling by fibroblast growth factor receptors publication-title: Cytokine Growth Factor Rev. – volume: 19 start-page: 51 year: 2014 end-page: 62 ident: bib0030 article-title: Current strategies for inhibiting FGFR activities in clinical applications: opportunities, challenges and toxicological considerations publication-title: Drug Discov. Today – volume: 12 start-page: 559 year: 2007 end-page: 6571 ident: bib0035 article-title: Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition publication-title: Cancer Cell – volume: 51 start-page: 4632 year: 2008 end-page: 4640 ident: bib0045 article-title: Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor publication-title: J. Med. Chem. – volume: 19 start-page: 51 year: 2014 ident: 10.1016/j.cclet.2014.06.010_bib0030 article-title: Current strategies for inhibiting FGFR activities in clinical applications: opportunities, challenges and toxicological considerations publication-title: Drug Discov. Today doi: 10.1016/j.drudis.2013.07.021 – volume: 10 start-page: 116 year: 2010 ident: 10.1016/j.cclet.2014.06.010_bib0020 article-title: Fibroblast growth factor signalling: from development to cancer publication-title: Nat. Rev. Cancer doi: 10.1038/nrc2780 – volume: 12 start-page: 559 year: 2007 ident: 10.1016/j.cclet.2014.06.010_bib0035 article-title: Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition publication-title: Cancer Cell doi: 10.1016/j.ccr.2007.11.004 – volume: 110 start-page: 4214 year: 2007 ident: 10.1016/j.cclet.2014.06.010_bib0040 article-title: FGFR-1 regulates angiogenesis through cytokines interleukin-4 and pleiotrophin publication-title: Blood doi: 10.1182/blood-2007-01-067314 – volume: 60 start-page: 1 year: 1993 ident: 10.1016/j.cclet.2014.06.010_bib0005 article-title: Structural and functional diversity in the FGF receptor multigene family publication-title: Adv. Cancer Res. doi: 10.1016/S0065-230X(08)60821-0 – volume: 245 start-page: 57 year: 1989 ident: 10.1016/j.cclet.2014.06.010_bib0010 article-title: Purification and complementary DNA cloning of a receptor for basic fibroblast growth factor publication-title: Science doi: 10.1126/science.2544996 – volume: 16 start-page: 139 year: 2005 ident: 10.1016/j.cclet.2014.06.010_bib0015 article-title: Cellular signaling by fibroblast growth factor receptors publication-title: Cytokine Growth Factor Rev. doi: 10.1016/j.cytogfr.2005.01.001 – volume: 1823 start-page: 850 year: 2012 ident: 10.1016/j.cclet.2014.06.010_bib0025 article-title: Mechanisms of FGFR-mediated carcinogenesis publication-title: Biochim. Biophys. Acta doi: 10.1016/j.bbamcr.2012.01.004 – volume: 51 start-page: 4632 year: 2008 ident: 10.1016/j.cclet.2014.06.010_bib0045 article-title: Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor publication-title: J. Med. Chem. doi: 10.1021/jm800566m |
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| SubjectTerms | Activator Chemical probe Cycloalkyl[d]pyrimidine derivatives FGFR-1 个例 合成 嘧啶 小分子 激活作用 环烷基 类似物 |
| Title | Discovery and synthesis of N2,N4-substitued-cycloalkyl[d]pyrimidine 2,4-diamine analogs： The first examples of small-molecular FGFR-1 activator |
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