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 kinase, such as echinoderm microtubule-associated protein-like 4-ALK, have recently been found in patients with non-small cell lung cancer, breast, and colorectal patients. Research has focused on developing inhibitors for targeted therapy of these ALK-positive tumours. Because kinase inhibitors that target the inactive conformation are thought to be more specific than ATP-targeted inhibitors, we therefore investigated the possibility of using two known inhibitors targeting inactive kinases, doramapimod and sorafenib, to design new urea derivatives as ALK inhibitors. A homology model of ALK in its inactive conformation complexed to doramapimod or sorafenib was generated and it explained why doramapimod is a weak inhibitor and why sorafenib is not inhibiting ALK. Virtual screening of commercially available compounds using the homology model of ALK yielded hit compounds, which were tested using biochemical assays. The preliminary results from the assays were applied in the design and synthesis of a novel series of urea derivatives, which were tested for inhibitory potency on ALK. Structure-activity relationship results showed positions on the core structure that were enhancing or reducing the activity both for the isolated enzyme and in the cellular assays. Some compounds showed inhibition of purified ALK in the high nanomolar range and selective antiproliferative activity on ALK-positive cells.

Design, synthesis and biological activity of urea derivatives as anaplastic lymphoma kinase inhibitors

243rd National Meeting (2012)

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