ABSTRACT
Cyclin G associated kinase (GAK) emerged as a promising drug target for the treatment of viral infections. However, no potent and selective GAK inhibitors have been reported in the literature to date. This paper describes the discovery of isothiazolo[5,4-b]pyridines as selective GAK inhibitors, with the most potent congeners displaying low nanomolar binding affinity for GAK. Cocrystallization experiments revealed that these compounds behaved as classic type I ATP-competitive kinase inhibitors. In addition, we have demonstrated that these compounds exhibit a potent activity against hepatitis C virus (HCV) by inhibiting two temporally distinct steps in the HCV life cycle (i.e., viral entry and assembly). Hence, these GAK inhibitors represent chemical probes to study GAK function in different disease areas where GAK has been implicated (including viral infection, cancer, and Parkinson's disease).
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Hepatitis C/drug therapy , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyridines/chemistry , Pyridines/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacology , Cell Line , Crystallography, X-Ray , Hepacivirus/physiology , Hepatitis C/enzymology , Humans , Intracellular Signaling Peptides and Proteins/chemistry , Intracellular Signaling Peptides and Proteins/metabolism , Models, Molecular , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/metabolism , Virus Internalization/drug effectsABSTRACT
Isothiazolo[4,3-b]pyridines are known to be endowed with potent affinity for cyclin G associated kinase (GAK). In this paper, we expanded the structure-activity relationship study by broadening the structural variety at position 3 of the isothiazolo[4,3-b]pyridine scaffold. The most potent GAK ligands (displaying Kd values of less than 100 nM) within this series carry an alkoxy group at position 3 of the central scaffold. Unfortunately, these ligands display only modest antiviral activity against the hepatitis C virus.
ABSTRACT
DRAK2 emerged as a promising drug target for the treatment of autoimmune diseases and to prevent graft rejection after organ transplantation. Screening of a compound library in a DRAK2 binding assay led to the identification of an isothiazolo[5,4-b]pyridine derivative as a novel ligand for DRAK2, displaying a Kd value of 1.6 µM. Subsequent medicinal chemistry work led to the discovery of a thieno[2,3-b]pyridine derivative with strong DRAK2 binding affinity (Kd = 9 nM). Moreover, this compound also behaves as a functional inhibitor of DRAK2 enzymatic activity, displaying an IC50 value of 0.82 µM, although lacking selectivity, when tested against DRAK1. This paper describes for the first time functionally active dual DRAK1 and DRAK2 inhibitors that can be used as starting point for the synthesis of chemical tool compounds to study DRAK1 and DRAK2 biology, or they can be considered as hit compounds for hit-to-lead optimization campaigns in drug discovery programs.
Subject(s)
Apoptosis Regulatory Proteins/antagonists & inhibitors , Drug Discovery , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Humans , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacology , Structure-Activity RelationshipABSTRACT
Novel compounds termed lipophosphonoxins were prepared using a simple and efficient synthetic approach. The general structure of lipophosphonoxins consists of four modules: (i) a nucleoside module, (ii) an iminosugar module, (iii) a hydrophobic module (lipophilic alkyl chain), and (iv) a phosphonate linker module that holds together modules i-iii. Lipophosphonoxins displayed significant antibacterial properties against a panel of Gram-positive species, including multiresistant strains. The minimum inhibitory concentration (MIC) values of the best inhibitors were in the 1-12 µg/mL range, while their cytotoxic concentrations against human cell lines were significantly above this range. The modular nature of this artificial scaffold offers a large number of possibilities for further modifications/exploitation of these compounds.
Subject(s)
Anti-Bacterial Agents/chemistry , Nucleosides/chemistry , Organophosphonates/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Apoptosis/drug effects , Cell Survival/drug effects , Cells, Cultured , Drug Resistance, Multiple, Bacterial , Erythroid Precursor Cells/cytology , Erythroid Precursor Cells/drug effects , Fetal Blood , Gram-Positive Bacteria/drug effects , Humans , Hydrophobic and Hydrophilic Interactions , Microbial Sensitivity Tests , Nucleosides/chemical synthesis , Nucleosides/pharmacology , Organophosphonates/chemical synthesis , Organophosphonates/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Among the structurally diverse nucleoside phosphonic acids, several compounds possessing strong antiviral properties have been found. Our effort in this area was focused to the synthesis of novel compounds - pyrrolidine-based nucleoside phosphonic acids and their derivatives.
Subject(s)
Antiviral Agents/chemical synthesis , Nucleosides/chemical synthesis , Nucleotides/chemical synthesis , Pyrrolidines/chemistry , Antiviral Agents/chemistry , Nucleosides/chemistry , Nucleotides/chemistry , Organophosphonates/chemistryABSTRACT
A novel series of racemic piperidin-3-yl and piperidin-4-yl derivatives of nucleobases and their phosphonate derivatives were prepared.
Subject(s)
Nucleosides/chemical synthesis , Nucleotides/chemical synthesis , Piperidines/chemistry , Nucleosides/chemistry , Nucleotides/chemistryABSTRACT
A number of structurally diverse nucleoside phosphonic acids have been tested against human recombinant thymidine phosphorylase and human platelets supernatant using 2'-deoxy-5-nitrouridine as the substrate. We have selected several inhibitors working at micromolar level as lead structures for further evaluation.
