Abstract
A series of 2-amino-2,3-dihydro-1H-indene-5-carboxamides were designed and synthesized as new selective discoidin domain receptor 1 (DDR1) inhibitors. One of the representative compounds, 7f, bound with DDR1 with a Kd value of 5.9 nM and suppressed the kinase activity with an half-maximal (50%) inhibitory concentration value of 14.9 nM. 7f potently inhibited collagen-induced DDR1 signaling and epithelial-mesenchymal transition, dose-dependently suppressed colony formation of pancreatic cancer cells, and exhibited promising in vivo therapeutic efficacy in orthotopic mouse models of pancreatic cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Discoidin Domain Receptor 1 / antagonists & inhibitors*
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Discoidin Domain Receptor 1 / metabolism
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Drug Design
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Epithelial-Mesenchymal Transition / drug effects
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Humans
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Male
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Mice, Inbred C57BL
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / prevention & control*
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / prevention & control*
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Rats, Sprague-Dawley
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Tumor Stem Cell Assay
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Xenograft Model Antitumor Assays / methods*
Substances
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Antineoplastic Agents
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Discoidin Domain Receptor 1