1. Discovery of 4-amino-1H-pyrazolo[3,4-d]pyrimidin derivatives as novel discoidin domain receptor 1 (DDR1) inhibitors.
- Author
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Dong R, Zhou X, Wang M, Li W, Zhang JY, Zheng X, Tang KX, and Sun LP
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Discoidin Domain Receptor 1 metabolism, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Molecular Docking Simulation, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Pyrazoles chemical synthesis, Pyrazoles chemistry, Pyrimidines chemical synthesis, Pyrimidines chemistry, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Discoidin Domain Receptor 1 antagonists & inhibitors, Drug Discovery, Protein Kinase Inhibitors pharmacology, Pyrazoles pharmacology, Pyrimidines pharmacology
- Abstract
DDR1 is a receptor tyrosine kinase that is activated by triple-helical collagens and has become an attractive target for anticancer therapy given its involvement in tumor growth, metastasis development, and tumor dormancy. Several drugs on the market, such as dasatinib and nilotinib, were reported to potently suppress the function of DDR1 and show significant therapeutic benefits in a variety of preclinical tumor models. Whereas only a few selective DDR1 inhibitors were disclosed in recent years. A series of 4-amino-1H-pyrazolo[3,4-d]pyrimidin derivatives were designed and synthesized. All compounds were evaluated via DDR1 kinase inhibition assay and cell anti-proliferative assay. One of the representative compounds, 6c, suppressed DDR1 kinase activity with an IC
50 value of 44 nM and potently inhibited cell proliferation in DDR1-overexpressing cell lines HCT-116 and MDA-MB-231 with IC50 value of 4.00 and 3.36 μM respectively. Further molecular docking study revealed that 6c fitted ideally into DDR1 binding pocket and maintained the crucial hydrogen bonds with DDR1 kinase domain. Overall, these results suggest that the compound 6c is a potential DDR1 inhibitor deserving further investigation for cancer treatment., (Copyright © 2020 Elsevier Ltd. All rights reserved.)- Published
- 2021
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