bi-78d3 and Insulin-Resistance

bi-78d3 has been researched along with Insulin-Resistance* in 2 studies

Other Studies

2 other study(ies) available for bi-78d3 and Insulin-Resistance

Article	Year
Design, synthesis, and structure-activity relationship of substrate competitive, selective, and in vivo active triazole and thiadiazole inhibitors of the c-Jun N-terminal kinase. Journal of medicinal chemistry, 2009, Apr-09, Volume: 52, Issue:7 We report comprehensive structure-activity relationship studies on a novel series of c-Jun N-terminal kinase (JNK) inhibitors. The compounds are substrate competitive inhibitors that bind to the docking site of the kinase. The reported medicinal chemistry and structure-based optimizations studies resulted in the discovery of selective and potent thiadiazole JNK inhibitors that display promising in vivo activity in mouse models of insulin insensitivity. Topics: Activating Transcription Factor 2; Animals; Binding Sites; Diabetes Mellitus, Type 2; Drug Design; HeLa Cells; Humans; Hypoglycemic Agents; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Male; Mice; Phosphorylation; Protein Binding; Structure-Activity Relationship; Substrate Specificity; Thiadiazoles; Thiazoles; Triazoles	2009
Identification of a new JNK inhibitor targeting the JNK-JIP interaction site. Proceedings of the National Academy of Sciences of the United States of America, 2008, Oct-28, Volume: 105, Issue:43 JNK is a stress-activated protein kinase that modulates pathways implicated in a variety of disease states. JNK-interacting protein-1 (JIP1) is a scaffolding protein that enhances JNK signaling by creating a proximity effect between JNK and upstream kinases. A minimal peptide region derived from JIP1 is able to inhibit JNK activity both in vitro and in cell. We report here a series of small molecules JIP1 mimics that function as substrate competitive inhibitors of JNK. One such compound, BI-78D3, dose-dependently inhibits the phosphorylation of JNK substrates both in vitro and in cell. In animal studies, BI-78D3 not only blocks JNK dependent Con A-induced liver damage but also restores insulin sensitivity in mouse models of type 2 diabetes. Our findings open the way for the development of protein kinase inhibitors targeting substrate specific docking sites, rather than the highly conserved ATP binding sites. In view of its favorable inhibition profile, selectivity, and ability to function in the cellular milieu and in vivo, BI-78D3 represents not only a JNK inhibitor, but also a promising stepping stone toward the development of an innovative class of therapeutics. Topics: Adaptor Proteins, Signal Transducing; Animals; Binding, Competitive; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Experimental; Dioxanes; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Liver Diseases; Mice; Molecular Mimicry; Phosphorylation; Protein Binding; Protein Kinase Inhibitors; Signal Transduction; Thiazoles	2008

Article

Year

Design, synthesis, and structure-activity relationship of substrate competitive, selective, and in vivo active triazole and thiadiazole inhibitors of the c-Jun N-terminal kinase.

Journal of medicinal chemistry, 2009, Apr-09, Volume: 52, Issue:7

We report comprehensive structure-activity relationship studies on a novel series of c-Jun N-terminal kinase (JNK) inhibitors. The compounds are substrate competitive inhibitors that bind to the docking site of the kinase. The reported medicinal chemistry and structure-based optimizations studies resulted in the discovery of selective and potent thiadiazole JNK inhibitors that display promising in vivo activity in mouse models of insulin insensitivity.

Topics: Activating Transcription Factor 2; Animals; Binding Sites; Diabetes Mellitus, Type 2; Drug Design; HeLa Cells; Humans; Hypoglycemic Agents; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Male; Mice; Phosphorylation; Protein Binding; Structure-Activity Relationship; Substrate Specificity; Thiadiazoles; Thiazoles; Triazoles

2009

Identification of a new JNK inhibitor targeting the JNK-JIP interaction site.

Proceedings of the National Academy of Sciences of the United States of America, 2008, Oct-28, Volume: 105, Issue:43

JNK is a stress-activated protein kinase that modulates pathways implicated in a variety of disease states. JNK-interacting protein-1 (JIP1) is a scaffolding protein that enhances JNK signaling by creating a proximity effect between JNK and upstream kinases. A minimal peptide region derived from JIP1 is able to inhibit JNK activity both in vitro and in cell. We report here a series of small molecules JIP1 mimics that function as substrate competitive inhibitors of JNK. One such compound, BI-78D3, dose-dependently inhibits the phosphorylation of JNK substrates both in vitro and in cell. In animal studies, BI-78D3 not only blocks JNK dependent Con A-induced liver damage but also restores insulin sensitivity in mouse models of type 2 diabetes. Our findings open the way for the development of protein kinase inhibitors targeting substrate specific docking sites, rather than the highly conserved ATP binding sites. In view of its favorable inhibition profile, selectivity, and ability to function in the cellular milieu and in vivo, BI-78D3 represents not only a JNK inhibitor, but also a promising stepping stone toward the development of an innovative class of therapeutics.

Topics: Adaptor Proteins, Signal Transducing; Animals; Binding, Competitive; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Experimental; Dioxanes; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Liver Diseases; Mice; Molecular Mimicry; Phosphorylation; Protein Binding; Protein Kinase Inhibitors; Signal Transduction; Thiazoles

2008