Screening and identification of novel compounds with potential anti-proliferative effects on gallium-resistant lung cancer through an AXL kinase pathway.
Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology; Antitumor; AXL; Cell Line; Cell Proliferation/drug effects; Cell Survival/drug effects; Dose-Response Relationship; Drug; Drug Resistance; Drug Screening Assays; Gallium; Gallium-resistance; Gallium/pharmacology; Humans; Lung cancer; Lung Neoplasms/drug therapy/*enzymology/*pathology; Molecular Structure; Naphthalenes/chemistry/*pharmacology; Neoplasm/drug effects; Proto-Oncogene Proteins/*antagonists & inhibitors/metabolism; Pyrazoles/chemistry/*pharmacology; Quinolines/chemistry/*pharmacology; Receptor Protein-Tyrosine Kinases/*antagonists & inhibitors/metabolism; Structure-Activity Relationship; Tetrazoles/chemistry/*pharmacology; Tumor; Virtual screening
The clinical application of gallium compounds as anticancer agents is hampered by development of resistance. As a potential strategy to overcome the limitation, eight series of compounds were identified through virtual screening of AXL kinase homology model. Anti-proliferative studies were carried using gallium-sensitive (S) and gallium-resistant (R) human lung adenocarcinoma (A549) cells. Compounds 5476423 and 7919469 were identified as leads. The IC50 values from treating
Oyewumi Moses O; Alazizi Adnan; Liva Sophia; Lin Li; Geldenhuys Werner J
Bioorganic & medicinal chemistry letters
2014
2014-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bmcl.2014.07.072" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2014.07.072</a>
Molecular determinants of blood-brain barrier permeation.
Humans; Animals; *Drug Delivery Systems; Blood-Brain Barrier/*metabolism; Brain/drug effects; Computer Simulation; high-throughput; in silico; logPS; nutrient transporters; Permeability; virtual screening
The blood-brain barrier (BBB) is a microvascular unit which selectively regulates the permeability of drugs to the brain. With the rise in CNS drug targets and diseases, there is a need to be able to accurately predict a priori which compounds in a company database should be pursued for favorable properties. In this review, we will explore the different computational tools available today, as well as underpin these to the experimental methods used to determine BBB permeability. These include in vitro models and the in vivo models that yield the dataset we use to generate predictive models. Understanding of how these models were experimentally derived determines our accurate and predicted use for determining a balance between activity and BBB distribution.
Geldenhuys Werner J; Mohammad Afroz S; Adkins Chris E; Lockman Paul R
Therapeutic delivery
2015
1905-7
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.4155/tde.15.32" target="_blank" rel="noreferrer noopener">10.4155/tde.15.32</a>