ABSTRACT
Selective inhibition of the RGD (Arg-Gly-Asp) integrin αvß1 has been recently identified as an attractive therapeutic approach for the treatment of liver fibrosis given its function, target expression, and safety profile. Our identification of a non-RGD small molecule lead followed by focused, systematic changes to the core structure utilizing a crystal structure, in silico modeling, and a tractable synthetic approach resulted in the identification of a potent small molecule exhibiting a remarkable affinity for αvß1 relative to several other integrin isoforms measured. Azabenzimidazolone 25 demonstrated antifibrotic efficacy in an in vivo rat liver fibrosis model and represents a tool compound capable of further exploring the biological consequences of selective αvß1 inhibition.
ABSTRACT
[This corrects the article DOI: 10.1021/acsmedchemlett.6b00481.].
ABSTRACT
Apoptosis signal-regulating kinase 1 (ASK1/MAP3K) is a mitogen-activated protein kinase family member shown to contribute to acute ischemia/reperfusion injury. Using structure-based drug design, deconstruction, and reoptimization of a known ASK1 inhibitor, a lead compound was identified. This compound displayed robust MAP3K pathway inhibition and reduction of infarct size in an isolated perfused heart model of cardiac injury.
ABSTRACT
Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
Subject(s)
Drug Discovery , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Pyrrolidinones/pharmacology , Syk Kinase/antagonists & inhibitors , Animals , Antineoplastic Agents , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mice , Mice, Inbred C57BL , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Pyrrolidinones/administration & dosage , Pyrrolidinones/chemistry , Structure-Activity Relationship , Syk Kinase/metabolismABSTRACT
Methionine aminopeptidase 2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. Pre-clinical and clinical studies suggest that MetAP2 inhibitors could be used as a novel treatment for obesity. Herein we describe our use of fragment screening methods and structural biology to quickly identify and elaborate an indazole fragment into a series of reversible MetAP2 inhibitors with <10nM potency, excellent selectivity, and favorable in vitro safety profiles.
Subject(s)
Aminopeptidases/antagonists & inhibitors , Body Weight/drug effects , Drug Discovery , Enzyme Inhibitors/pharmacology , Glycoproteins/antagonists & inhibitors , Indazoles/pharmacology , Obesity/drug therapy , Administration, Oral , Aminopeptidases/metabolism , Animals , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Glycoproteins/metabolism , Humans , Indazoles/chemical synthesis , Indazoles/chemistry , Methionyl Aminopeptidases , Mice , Mice, Obese , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
Guided by co-crystal structures of compounds 15, 22 and 30, an SBDD approach led to the discovery of the 6-methyl pyridone series as a novel class of GKAs that potently activate GK in enzyme and cell assays. Anti-diabetic OGTT efficacy was demonstrated with 54 in a mouse model of type 2 diabetes.
