ABSTRACT
Starting from benzylpyrimidine 2, molecular modeling and X-ray crystallography were used to design highly potent inhibitors of Interleukin-2 inducible T-cell kinase (ITK). Sulfonylpyridine 4i showed sub-nanomolar affinity against ITK, was selective versus Lck and its activity in the Jurkat cell-based assay was greatly improved over 2.
Subject(s)
Drug Design , Protein Kinase Inhibitors/chemical synthesis , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyridines/chemistry , Binding Sites , Crystallography, X-Ray , Kinetics , Molecular Dynamics Simulation , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Structure, Tertiary , Protein-Tyrosine Kinases/metabolism , Pyrazoles/chemistry , Pyridines/chemical synthesis , Pyridines/metabolism , Structure-Activity Relationship , Sulfones/chemistryABSTRACT
Heat-shock protein 90 (Hsp90) is a molecular chaperone involved in the stabilization of key oncogenic signaling proteins, and therefore, inhibition of Hsp90 represents a new strategy in cancer therapy. 2-Amino-7-[4-fluoro-2-(3-pyridyl)phenyl]-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime is a racemic Hsp90 inhibitor that targets the N-terminal adenosine triphosphatase site. We developed a method to resolve the enantiomers and evaluated their inhibitory activity on Hsp90 and the consequent antitumor effects. The (S) stereoisomer emerged as a potent Hsp90 inhibitor in biochemical and cellular assays. In addition, this enantiomer exhibited high oral bioavailability in mice and excellent antitumor activity in two different human cancer xenograft models.
Subject(s)
Antineoplastic Agents/chemistry , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Oximes/chemistry , Quinazolinones/chemistry , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Binding Sites , Cell Line, Tumor , Female , HCT116 Cells , HSP90 Heat-Shock Proteins/metabolism , Humans , Mice , Mice, Nude , Microsomes/metabolism , Molecular Docking Simulation , Neoplasms/drug therapy , Oximes/pharmacology , Oximes/therapeutic use , Protein Binding/drug effects , Protein Structure, Tertiary , Stereoisomerism , Xenograft Model Antitumor AssaysABSTRACT
Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cellular activity and kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of several inhibitor-ITK complexes.
Subject(s)
Benzothiazoles/chemistry , Benzothiazoles/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Benzothiazoles/chemical synthesis , Crystallography, X-Ray , Drug Design , Humans , Mice , Models, Molecular , Protein-Tyrosine Kinases/chemistry , Signal Transduction , Structure-Activity RelationshipABSTRACT
PKCα and PKA have crucial but opposing roles in the regulation of calcium handling within myocytes. Identification of compounds that inhibit PKCα, but not PKA, are potential therapeutic targets for the treatment of heart disease. The synthesis of indolylureas are described, and a compound displaying nanomolar inhibition towards PKCα with significant selectivity over PKA has been identified.
Subject(s)
Protein Kinase C-alpha/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Urea/chemical synthesis , Urea/pharmacology , Cyclic AMP-Dependent Protein Kinases , Heart Diseases/drug therapy , Humans , Urea/chemistrySubject(s)
Adenine/analogs & derivatives , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Pyrazoles/chemistry , Adenine/chemical synthesis , Adenine/chemistry , Adenine/pharmacology , Binding Sites , Computer Simulation , Drug Evaluation, Preclinical , HSP90 Heat-Shock Proteins/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , ThermodynamicsABSTRACT
(1,1-Dioxo-2H-[1,2,4]benzothiadiazin-3-yl) azolo[1,5-a]pyridine and azolo[1,5-a]pyrimidine derivatives have been investigated as potential anti-HCV drugs. Their synthesis, HCV NS5B polymerase inhibition, and replicon activity are discussed.
Subject(s)
Antiviral Agents/chemical synthesis , Azoles/chemical synthesis , Benzothiadiazines/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Hepatitis C/drug therapy , Pyridines/chemical synthesis , Pyrimidines/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/pharmacology , Azoles/pharmacology , Benzothiadiazines/pharmacology , Chemistry, Pharmaceutical/methods , Drug Design , Enzyme Inhibitors/pharmacology , Hepacivirus/metabolism , In Vitro Techniques , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Models, Chemical , Molecular Structure , Pyridines/pharmacology , Pyrimidines/pharmacology , Structure-Activity Relationship , Viral Nonstructural Proteins/chemistryABSTRACT
Heat shock protein 90 (Hsp90) plays a key role in stress response and protection of the cell against the effects of mutation. Herein we report the identification of an Hsp90 inhibitor identified by fragment screening using a high-concentration biochemical assay, as well as its optimisation by in silico searching coupled with a structure-based drug design (SBDD) approach.
