{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T03:17:18Z","timestamp":1791256638090,"version":"4.1.0"},"reference-count":51,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T00:00:00Z","timestamp":1711497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Korea Institute of Science and Technology","award":["2E32852"],"award-info":[{"award-number":["2E32852"]}]},{"name":"Korea Institute of Science and Technology","award":["2019H1D3A1A01070882"],"award-info":[{"award-number":["2019H1D3A1A01070882"]}]},{"name":"Korea Institute of Science and Technology","award":["NRF-2021M3E5E3080563"],"award-info":[{"award-number":["NRF-2021M3E5E3080563"]}]},{"name":"Korea Research Fellowship (KRF)","award":["2E32852"],"award-info":[{"award-number":["2E32852"]}]},{"name":"Korea Research Fellowship (KRF)","award":["2019H1D3A1A01070882"],"award-info":[{"award-number":["2019H1D3A1A01070882"]}]},{"name":"Korea Research Fellowship (KRF)","award":["NRF-2021M3E5E3080563"],"award-info":[{"award-number":["NRF-2021M3E5E3080563"]}]},{"name":"Ministry of Science and ICT","award":["2E32852"],"award-info":[{"award-number":["2E32852"]}]},{"name":"Ministry of Science and ICT","award":["2019H1D3A1A01070882"],"award-info":[{"award-number":["2019H1D3A1A01070882"]}]},{"name":"Ministry of Science and ICT","award":["NRF-2021M3E5E3080563"],"award-info":[{"award-number":["NRF-2021M3E5E3080563"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Discoidin domain receptor 1 (DDR1) kinase has emerged as a promising target for cancer therapy, and selective DDR1 inhibitors have shown promise as effective therapeutic candidates. Herein, we have identified the first coumarin-based selective DDR1 inhibitors via repurposing of a recent series of carbonic anhydrase inhibitors. Among these, ureidocoumarins 3a, 3i, and 3q showed the best DDR1 inhibitory activities. The m-trifluoromethoxy phenyl member 3q potently inhibited DDR1 with an IC50 of 191 nM, while it showed less inhibitory activity against DDR2 (IC50 = 5080 nM). 3q also exhibited favorable selectivity in a screening platform with 23 common off-target kinases, including BCR-ABL. In the cellular context, 3q showed moderate antiproliferative effects, while 3i, with the third rank in DDR1 inhibition, exerted the best anticancer activity with sub-micromolar GI50 values over certain DDR1-dependent cell lines. Molecular docking and MD simulations disclosed the putative binding mode of this coumarin chemotype and provided insights for further optimization of this scaffold. The present findings collectively supported the potential improvement of ureidocoumarins 3i and 3q for cancer treatment.<\/jats:p>","DOI":"10.3390\/ph17040427","type":"journal-article","created":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T14:14:09Z","timestamp":1711548849000},"page":"427","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Identification of Ureidocoumarin-Based Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors via Drug Repurposing Approach, Biological Evaluation, and In Silico Studies"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8446-0383","authenticated-orcid":false,"given":"Ashraf K.","family":"El-Damasy","sequence":"first","affiliation":[{"name":"Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea"},{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Ji","family":"Kim","sequence":"additional","affiliation":[{"name":"Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8173-6073","authenticated-orcid":false,"given":"Ahmed A.","family":"Al-Karmalawy","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt"},{"name":"Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City 12566, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1869-9596","authenticated-orcid":false,"given":"Radwan","family":"Alnajjar","sequence":"additional","affiliation":[{"name":"CADD Unit, Faculty of Pharmacy, Libyan International Medical University, Benghazi 16063, Libya"},{"name":"Department of Chemistry, Faculty of Science, University of Benghazi, Benghazi 16063, Libya"},{"name":"Department of Chemistry, University of Cape Town, Rondebosch 7700, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8146-993X","authenticated-orcid":false,"given":"Mohamed M.","family":"Khalifa","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Medicinal Chemistry & Drug Design, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun-Kyoung","family":"Bang","sequence":"additional","affiliation":[{"name":"Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8767-8022","authenticated-orcid":false,"given":"Gyochang","family":"Keum","sequence":"additional","affiliation":[{"name":"Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"12114","DOI":"10.1074\/jbc.M112.409599","article-title":"Shedding of discoidin domain receptor 1 by membrane-type matrix metalloproteinases","volume":"288","author":"Fu","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/s10555-012-9346-z","article-title":"Discoidin domain receptor tyrosine kinases: New players in cancer progression","volume":"31","author":"Valiathan","year":"2012","journal-title":"Cancer Metastasis Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3287","DOI":"10.1021\/jm5012319","article-title":"Small Molecule Discoidin Domain Receptor Kinase Inhibitors and Potential Medical Applications: Miniperspective","volume":"58","author":"Li","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_4","first-page":"1435","article-title":"Overexpression of discoidin domain receptor 1 increases the migration and invasion of hepatocellular carcinoma cells in association with matrix metalloproteinase","volume":"18","author":"Park","year":"2007","journal-title":"Oncol. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s11060-006-9246-6","article-title":"Enhancement of pituitary adenoma cell invasion and adhesion is mediated by discoidin domain receptor-1","volume":"82","author":"Yoshida","year":"2007","journal-title":"J. Neuro-Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Elkamhawy, A., Lu, Q., Nada, H., Woo, J., Quan, G., and Lee, K. (2021). The journey of DDR1 and DDR2 kinase inhibitors as rising stars in the fight against cancer. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126535"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1007\/s00044-020-02694-2","article-title":"DDR1 and DDR2: A review on signaling pathway and small molecule inhibitors as an anticancer agent","volume":"30","author":"Matada","year":"2021","journal-title":"Med. Chem. Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Yamaoka, T., Kusumoto, S., Ando, K., Ohba, M., and Ohmori, T. (2018). Receptor tyrosine kinase-targeted cancer therapy. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113491"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.ijbiomac.2020.12.009","article-title":"Tyrosine kinase inhibitors and their unique therapeutic potentialities to combat cancer","volume":"168","author":"Zhao","year":"2021","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1007\/s12272-020-01232-3","article-title":"Small molecule tyrosine kinase inhibitors in glioblastoma","volume":"43","author":"Kim","year":"2020","journal-title":"Arch. Pharmacal Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1111\/gtc.12022","article-title":"Activity-based kinase profiling of approved tyrosine kinase inhibitors","volume":"18","author":"Kitagawa","year":"2013","journal-title":"Genes Cells"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1038\/nbt.1990","article-title":"Comprehensive analysis of kinase inhibitor selectivity","volume":"29","author":"Davis","year":"2011","journal-title":"Nat. Biotechnol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.ejphar.2008.10.014","article-title":"Inhibition of collagen-induced discoidin domain receptor 1 and 2 activation by imatinib, nilotinib and dasatinib","volume":"599","author":"Day","year":"2008","journal-title":"Eur. J. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1038\/nbt1328","article-title":"Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors","volume":"25","author":"Bantscheff","year":"2007","journal-title":"Nat. Biotechnol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/leu.2009.228","article-title":"A comprehensive target selectivity survey of the BCR-ABL kinase inhibitor INNO-406 by kinase profiling and chemical proteomics in chronic myeloid leukemia cells","volume":"24","author":"Rix","year":"2010","journal-title":"Leukemia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1021\/jm301581y","article-title":"Identification of GZD824 as an orally bioavailable inhibitor that targets phosphorylated and nonphosphorylated breakpoint cluster region\u2013abelson (Bcr-Abl) kinase and overcomes clinically acquired mutation-induced resistance against imatinib","volume":"56","author":"Ren","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s40268-019-0266-z","article-title":"Multikinase Abl\/DDR\/Src inhibition produces optimal effects for tyrosine kinase inhibition in neurodegeneration","volume":"19","author":"Fowler","year":"2019","journal-title":"Drugs R&D"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1002\/cmdc.201600224","article-title":"Discovery of a Nanomolar Multikinase Inhibitor (KST016366): A New Benzothiazole Derivative with Remarkable Broad-Spectrum Antiproliferative Activity","volume":"11","author":"Cho","year":"2016","journal-title":"Chemmedchem"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3281","DOI":"10.1021\/jm301824k","article-title":"Discovery and Optimization of 3-(2-(Pyrazolo [1,5-a]pyrimidin-6-yl)-ethynyl)benzamides as Novel Selective and Orally Bioavailable Discoidin Domain Receptor 1 (DDR1) Inhibitors","volume":"56","author":"Gao","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2145","DOI":"10.1021\/cb400430t","article-title":"Discovery of a Potent and Selective DDR1 Receptor Tyrosine Kinase Inhibitor","volume":"8","author":"Kim","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1021\/acsmedchemlett.9b00382","article-title":"Discovery of VU6015929: A Selective Discoidin Domain Receptor 1\/2 (DDR1\/2) Inhibitor to Explore the Role of DDR1 in Antifibrotic Therapy","volume":"11","author":"Jeffries","year":"2020","journal-title":"Acs Med. Chem. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"158","DOI":"10.3109\/14756366.2015.1004057","article-title":"Discovery of a broad spectrum antiproliferative agent with selectivity for DDR1 kinase: Cell line-based assay, kinase panel, molecular docking, and toxicity studies","volume":"31","author":"Elkamhawy","year":"2016","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4252","DOI":"10.1021\/jm500167q","article-title":"Identification of Type II and III DDR2 Inhibitors","volume":"57","author":"Richters","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_24","unstructured":"Tsutsui, H., Okimura, K., Udagawa, S., Kaino, M., Meguro, H., and Sekiya, Y. (2017). Preparation of N-(2,3-dihydro-1H-inden-1-yl)-N\u2019-[3-(pentafluorosulfanyl)phenyl]urea Derivatives as Inhibitors of Discoidin Domain Receptor Kinase 1 (DDR1). (WO 2017038870), World patent."},{"key":"ref_25","unstructured":"Nishio, Y., Kubota, Y., Yamamoto, M., Nishimura, Y., Masuda, T., Tsutsui, H., Okimura, K., Udagawa, S., Kaino, M., and Meguro, H. (2017). Preparation of Urea Derivatives for Inhibiting Discoidin Domain Receptor 1. (WO 2017038873 A1), World patent."},{"key":"ref_26","unstructured":"Nishio, Y., Yamamoto, M., Kubota, Y., Tsutsui, H., Masuda, T., Okimura, K., Udagawa, S., Kaino, M., Meguro, H., and Sekiya, Y. (2017). Preparation of Urea Derivatives for Inhibiting Discoidin Domain Receptor 1. (WO 2017038871), World patent."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1021\/acsmedchemlett.5b00143","article-title":"Fragment-based discovery of potent and selective DDR1\/2 inhibitors","volume":"6","author":"Murray","year":"2015","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.ddstr.2011.10.002","article-title":"2011. Drug repurposing from an academic perspective","volume":"8","author":"Oprea","year":"2011","journal-title":"Drug Discov. Today Ther. Strateg."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrd.2018.168","article-title":"Drug repurposing: Progress, challenges and recommendations","volume":"18","author":"Pushpakom","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2154603","DOI":"10.1080\/14756366.2022.2154603","article-title":"Discovery of new 6-ureido\/amidocoumarins as highly potent and selective inhibitors for the tumour-relevant carbonic anhydrases IX and XII","volume":"38","author":"Kim","year":"2023","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_31","unstructured":"Murata, T., Niizuma, S., Hara, S., Kawada, H., Hada, K., Shimada, H., Tanaka, H., and Nakanishi, Y. (2013). Preparation of benzamide derivatives as discoidin domain receptor 1 (DDR1) inhibitors. (WO2013161851), World patent."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1007\/s00044-023-03066-2","article-title":"Novel potent and highly selective DDR1 inhibitors from integrated lead finding","volume":"32","author":"Kuhn","year":"2023","journal-title":"Med. Chem. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3080","DOI":"10.1080\/00397911.2020.1792498","article-title":"Polyphosphoric acid-promoted synthesis of coumarins lacking substituents at positions 3 and 4","volume":"50","author":"Yang","year":"2020","journal-title":"Synth. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1002\/cmdc.202000915","article-title":"Coumarin-Thiourea Hybrids Show Potent Carbonic Anhydrase IX and XIII Inhibitory Action","volume":"16","author":"Thacker","year":"2021","journal-title":"Chemmedchem"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1002\/cmdc.201700446","article-title":"Sulfocoumarin-, Coumarin-, 4-Sulfamoylphenyl-Bearing Indazole-3-carboxamide Hybrids: Synthesis and Selective Inhibition of Tumor-Associated Carbonic Anhydrase Isozymes IX and XII","volume":"12","author":"Angapelly","year":"2017","journal-title":"Chemmedchem"},{"key":"ref_36","unstructured":"(2024, February 10). Available online: https:\/\/www.way2drug.com\/KinScreen\/."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.1021\/acs.jmedchem.5b00104","article-title":"pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures","volume":"58","author":"Pires","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_38","unstructured":"(2024, February 10). Reaction Biology Corporation. Available online: http:\/\/www.reactionbiology.com\/webapps\/site\/Kinase_Assay_Protocol.aspx."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5596","DOI":"10.1016\/j.bmc.2018.10.004","article-title":"Novel 5,6-disubstituted pyrrolo [2,3-d]pyrimidine derivatives as broad spectrum antiproliferative agents: Synthesis, cell based assays, kinase profile and molecular docking study","volume":"26","author":"Lee","year":"2018","journal-title":"Bioorganic Med. Chem."},{"key":"ref_40","unstructured":"(2024, February 10). DTP Human Tumor Cell Line Screen Process, Available online: https:\/\/dtp.cancer.gov\/discovery_development\/nci-60\/methodology.htm."},{"key":"ref_41","unstructured":"(2022). Schr\u00f6dinger Release 2022-1: Maestro, Schr\u00f6dinger, LLC."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4291","DOI":"10.1021\/acs.jctc.1c00302","article-title":"OPLS4: Improving force field accuracy on challenging regimes of chemical space","volume":"17","author":"Lu","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014A visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_44","unstructured":"Release, S. (2017). Maestro-Desmond Interoperability Tools, Schr\u00f6dinger."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2794","DOI":"10.1002\/prot.23106","article-title":"The VSGB 2.0 model: A next generation energy model for high resolution protein structure modeling","volume":"79","author":"Li","year":"2011","journal-title":"Proteins"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1021\/acs.jctc.5b00864","article-title":"OPLS3: A force field providing broad coverage of drug-like small molecules and proteins","volume":"12","author":"Harder","year":"2016","journal-title":"J. Chem. Theory Comput."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1902","DOI":"10.1063\/1.472061","article-title":"Simulation of activation free energies in molecular systems","volume":"105","author":"Neria","year":"1996","journal-title":"J. Chem. Phys."},{"key":"ref_49","unstructured":"Manual, D.U. (2024, March 20). Desmond2. 2. Available online: https:\/\/www.cines.fr\/wp-content\/uploads\/2014\/01\/des22_user_manual.pdf."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2635","DOI":"10.1063\/1.463940","article-title":"Nos\u00e9\u2013Hoover chains: The canonical ensemble via continuous dynamics","volume":"97","author":"Martyna","year":"1992","journal-title":"J. Chem. Phys."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4177","DOI":"10.1063\/1.467468","article-title":"Constant pressure molecular dynamics algorithms","volume":"101","author":"Martyna","year":"1994","journal-title":"J. Chem. Phys."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/4\/427\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:19:24Z","timestamp":1760105964000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/4\/427"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,27]]},"references-count":51,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["ph17040427"],"URL":"https:\/\/doi.org\/10.3390\/ph17040427","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,27]]}}}