Design, synthesis, and biological activity of urea derivatives as anaplastic lymphoma kinase inhibitors |
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Authors: | af Gennäs Gustav Boije Mologni Luca Ahmed Shaheen Rajaratnam Mohanathas Marin Oriano Lindholm Niko Viltadi Michela Gambacorti-Passerini Carlo Scapozza Leonardo Yli-Kauhaluoma Jari |
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Affiliation: | 1. Division of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, P.O. Box 56 (Viikinkaari 5?E), 00014 Helsinki (Finland), Fax: (+358)?9‐191‐59556;2. Department of Clinical Medicine and Prevention, University of Milano‐Bicocca, Via Cadore 48, 20052 Monza (Italy), Fax: (+39)?039‐233‐3539;3. Group of Pharmaceutical Biochemistry, School of Pharmaceutical Sciences, University of Geneva, Quai Ernest‐Ansermet 30, 1211 Genève 4 (Switzerland), Fax: (+41)?22‐379‐3360;4. Peptide Facility, CRIBI‐Biotechnology Centre, University of Padova, Viale Colombo 3, 35131 Padova (Italy) |
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Abstract: | In anaplastic large-cell lymphomas, chromosomal translocations involving the kinase domain of anaplastic lymphoma kinase (ALK), generally fused to the 5' part of the nucleophosmin gene, produce highly oncogenic ALK fusion proteins that deregulate cell cycle, apoptosis, and differentiation in these cells. Other fusion oncoproteins involving ALK, such as echinoderm microtubule-associated protein-like 4-ALK, were recently found in patients with non-small-cell lung, breast, and colorectal cancers. Recent research has focused on the development of inhibitors for targeted therapy of these ALK-positive tumors. Because kinase inhibitors that target the inactive conformation are thought to be more specific than ATP-targeted inhibitors, we investigated the possibility of using two known inhibitors, doramapimod and sorafenib, which target inactive kinases, to design new urea derivatives as ALK inhibitors. We generated a homology model of ALK in its inactive conformation complexed with doramapimod or sorafenib in its active site. The results elucidated why doramapimod is a weak inhibitor and why sorafenib does not inhibit ALK. Virtual screening of commercially available compounds using the homology model of ALK yielded candidate inhibitors, which were tested using biochemical assays. Herein we present the design, synthesis, biological activity, and structure-activity relationships of a novel series of urea compounds as potent ALK inhibitors. Some compounds showed inhibition of purified ALK in the high nanomolar range and selective antiproliferative activity on ALK-positive cells. |
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Keywords: | anaplastic lymphoma kinase antitumor agents inhibitors medicinal chemistry structure–activity relationships |
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