1.NMR reveals the allosteric opening and closing of Abelson tyrosine kinase by ATP-site and myristoyl pocket inhibitors.
Skora L;Mestan J;Fabbro D;Jahnke W;Grzesiek S Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):E4437-45. doi: 10.1073/pnas.1314712110. Epub 2013 Nov 4.
Successful treatment of chronic myelogenous leukemia is based on inhibitors binding to the ATP site of the deregulated breakpoint cluster region (Bcr)-Abelson tyrosine kinase (Abl) fusion protein. Recently, a new type of allosteric inhibitors targeting the Abl myristoyl pocket was shown in preclinical studies to overcome ATP-site inhibitor resistance arising in some patients. Using NMR and small-angle X-ray scattering, we have analyzed the solution conformations of apo Abelson tyrosine kinase (c-Abl) and c-Abl complexes with ATP-site and allosteric inhibitors. Binding of the ATP-site inhibitor imatinib leads to an unexpected open conformation of the multidomain SH3-SH2-kinase c-Abl core, whose relevance is confirmed by cellular assays on Bcr-Abl. The combination of imatinib with the allosteric inhibitor GNF-5 restores the closed, inactivated state. Our data provide detailed insights on the poorly understood combined effect of the two inhibitor types, which is able to overcome drug resistance.
2.Targeting invadopodia-mediated breast cancer metastasis by using ABL kinase inhibitors.
Meirson T;Genna A;Lukic N;Makhnii T;Alter J;Sharma VP;Wang Y;Samson AO;Condeelis JS;Gil-Henn H Oncotarget. 2018 Apr 24;9(31):22158-22183. doi: 10.18632/oncotarget.25243. eCollection 2018 Apr 24.
Metastatic dissemination of cancer cells from the primary tumor and their spread to distant sites in the body is the leading cause of mortality in breast cancer patients. While researchers have identified treatments that shrink or slow metastatic tumors, no treatment that permanently eradicates metastasis exists at present. Here, we show that the ABL kinase inhibitors imatinib, nilotinib, and GNF-5 impede invadopodium precursor formation and cortactin-phosphorylation dependent invadopodium maturation, leading to decreased actin polymerization in invadopodia, reduced extracellular matrix degradation, and impaired matrix proteolysis-dependent invasion. Using a mouse xenograft model we demonstrate that, while primary tumor size is not affected by ABL kinase inhibitors, the ;in vivo; matrix metalloproteinase (MMP) activity, tumor cell invasion, and consequent spontaneous metastasis to lungs are significantly impaired in inhibitor-treated mice. Further proteogenomic analysis of breast cancer patient databases revealed co-expression of the Abl-related gene (Arg) and cortactin across all hormone- and human epidermal growth factor receptor 2 (HER2)-receptor status tumors, which correlates synergistically with distant metastasis and poor patient prognosis.
3.Role of Abl in airway hyperresponsiveness and airway remodeling.
Cleary RA;Wang R;Wang T;Tang DD Respir Res. 2013 Oct 11;14:105. doi: 10.1186/1465-9921-14-105.
BACKGROUND: ;Asthma is a chronic disease that is characterized by airway hyperresponsiveness and airway remodeling. The underlying mechanisms that mediate the pathological processes are not fully understood. Abl is a non-receptor protein tyrosine kinase that has a role in the regulation of smooth muscle contraction and smooth muscle cell proliferation in vitro. The role of Abl in airway hyperresponsiveness and airway remodeling in vivo is largely unknown.;METHODS: ;To evaluate the role of Abl in asthma pathology, we assessed the expression of Abl in airway tissues from the ovalbumin sensitized and challenged mouse model, and human asthmatic airway smooth muscle cells. In addition, we generated conditional knockout mice in which Abl expression in smooth muscle was disrupted, and then evaluated the effects of Abl conditional knockout on airway resistance, smooth muscle mass, cell proliferation, IL-13 and CCL2 in the mouse model of asthma. Furthermore, we determined the effects of the Abl pharmacological inhibitors imatinib and GNF-5 on these processes in the animal model of asthma.;RESULTS: ;The expression of Abl was upregulated in airway tissues of the animal model of asthma and in airway smooth muscle cells of patients with severe asthma.
CAS No.: 778277-15-9
