Premium
Design, Synthesis, and Biological Activity of Urea Derivatives as Anaplastic Lymphoma Kinase Inhibitors
Author(s) -
Boije af Gennäs Gustav,
Mologni Luca,
Ahmed Shaheen,
Rajaratnam Mohanathas,
Marin Oriano,
Lindholm Niko,
Viltadi Michela,
GambacortiPasserini Carlo,
Scapozza Leonardo,
YliKauhaluoma Jari
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100168
Subject(s) - anaplastic lymphoma kinase , alk inhibitor , anaplastic large cell lymphoma , cancer research , kinase , chemistry , sorafenib , biochemistry , biology , lymphoma , medicine , lung cancer , hepatocellular carcinoma , malignant pleural effusion , immunology
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.