Structural Mechanisms Determining Inhibition of the Collagen Receptor DDR1 by Selective and Multi-Targeted Type II Kinase Inhibitors

The discoidin domain receptors (DDRs), DDR1 and DDR2, form a unique subfamily of receptor tyrosine kinases that are activated by the binding of triple-helical collagen. Excessive signaling by DDR1 and DDR2 has been linked to the progression of various human diseases, including fibrosis, atherosclerosis and cancer. We report the inhibition of these unusual receptor tyrosine kinases by the multi-targeted cancer drugs imatinib and ponatinib, as well as the selective type II inhibitor DDR1-IN-1. Ponatinib is identified as the more potent molecule, which inhibits DDR1 and DDR2 with an IC₅₀ of 9 nM. Co-crystal structures of human DDR1 reveal a DFG-out conformation (DFG, Asp-Phe-Gly) of the kinase domain that is stabilized by an unusual salt bridge between the activation loop and αD helix. Differences to Abelson kinase (ABL) are observed in the DDR1 P-loop, where a β-hairpin replaces the cage-like structure of ABL. P-loop residues in DDR1 that confer drug resistance in ABL are therefore accommodated outside the ATP pocket. Whereas imatinib and ponatinib bind potently to both the DDR and ABL kinases, the hydrophobic interactions of the ABL P-loop appear poorly satisfied by DDR1-IN-1 suggesting a structural basis for its DDR1 selectivity. Such inhibitors may have applications in clinical indications of DDR1 and DDR2 overexpression or mutation, including lung cancer.     

Naproxen and Cromolyn as New Glycogen Synthase Kinase 3β Inhibitors for Amelioration of Diabetes and Obesity: An Investigation by Docking Simulation and Subsequent In Vitro/In Vivo Biochemical Evaluation

Naproxen and cromolyn were investigated as new inhibitors of glycogen synthase kinase‐3β (GSK‐3β) in an attempt to explain their hypoglycemic properties. Study included simulated docking experiments, in vitro enzyme inhibition assay, and in vivo validations. Both drugs not only were optimally fitted within a GSK‐3β binding pocket via several attractive interactions with key amino acids but also exhibited potent in vitro enzymatic inhibitory activities of IC50 1.5 and 2.0 µM for naproxen and cromolyn, respectively. In vivo experiments illustrated that both drugs significantly reduced serum glucose and increased hepatic glycogen‐ and serum insulin levels in normal and type II diabetic Balb/c mice models. In obese animal model, both drugs exhibited significant reduction in mice weights, serum glucose, and resistin levels along with significant elevation in serum insulin, C‐peptide, and adiponectin values. It can be concluded that naproxen and cromolyn are novel GSK‐3β inhibitors and can help in management of diabetes and obesity. © 2013 Wiley Periodicals, Inc. J BiochemMol Toxicol 27:425–436, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/jbt.21503