ABSTRACT
Prolyl hydroxylases (PHDs) down-regulate the level of hypoxia-inducible factors (HIFs) by hydroxylating key proline residues that trigger the degradation of the protein and affect the cell and its ability to respond to hypoxic stress. Several small molecule PHD inhibitors are now in various preclinical and clinical stages for the treatment of anemia. The present study provides a detail kinetic analysis for some of these inhibitors. The data generated in the present study suggest that these compounds are reversible and compete directly with the co-substrate, 2-oxoglutarate (2-OG) for binding at the enzyme active site. Most of these compounds are pan PHD inhibitors and exhibit a time-dependent inhibition (TDI) mechanism due to an extremely slow dissociation rate constant, koff, and a long residence time.
Subject(s)
Enzyme Inhibitors/pharmacology , Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Catalytic Domain , Enzyme Inhibitors/chemistry , Humans , Hypoxia-Inducible Factor-Proline Dioxygenases/chemistry , Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism , Ketoglutaric Acids/metabolism , Kinetics , Protein Binding , Small Molecule Libraries/chemistryABSTRACT
Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Drug Design , Imidazoles/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Pteridines/chemical synthesis , Animals , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Female , HT29 Cells , Heterografts , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Mice , Molecular Structure , Pteridines/chemistry , Pteridines/pharmacology , Structure-Activity Relationship , Polo-Like Kinase 1ABSTRACT
Axl has been a target of interest in the oncology field for several years based on its role in various oncogenic processes. To date, no wild-type Axl crystal structure has been reported. Herein, we describe the structure-based optimization of a novel chemotype of Axl inhibitors, 1H-imidazole-2-carboxamide, using a mutated kinase homolog, Mer(I650M), as a crystallographic surrogate. Iterative optimization of the initial lead compound (1) led to compound (21), a selective and potent inhibitor of wild-type Axl. Compound (21) will serve as a useful compound for further in vivo studies.
Subject(s)
Imidazoles/chemistry , Imidazoles/pharmacology , Mutation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/genetics , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/genetics , Crystallography, X-Ray , Molecular Structure , c-Mer Tyrosine Kinase , Axl Receptor Tyrosine KinaseABSTRACT
Structure based drug design of a series of novel 1,4-benzoxazin-3-one derived PARP-1 inhibitors are described. The synthesis, enzymatic & cellular activities and pharmacodynamic effects are described. Optimized analogs demonstrated inhibition of poly-ADP-ribosylation in SW620 tumor bearing nude mice through 24h following a single dose.
Subject(s)
Benzoxazines/chemistry , Benzoxazines/pharmacology , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors , Animals , Cell Line, Tumor , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Humans , Mice , Mice, Nude , Molecular StructureABSTRACT
Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies.
Subject(s)
Azepines/chemistry , Azepines/pharmacology , Cell Cycle Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , 4-Aminobenzoic Acid/chemistry , 4-Aminobenzoic Acid/pharmacokinetics , 4-Aminobenzoic Acid/pharmacology , Administration, Oral , Adult , Azepines/pharmacokinetics , Cell Line, Tumor , Drug Discovery , Humans , Protein Kinase Inhibitors/pharmacokinetics , Young Adult , Polo-Like Kinase 1ABSTRACT
A highly convergent total synthesis of the potent anticancer agent (+)-phorboxazole A (1) is accomplished. Four components (3-6) are assembled with considerations for control of absolute and relative stereochemistry. Iterative asymmetric allylation methodology addresses key stereochemical features in the preparation of the 2,6-cis- and 2,6-trans-tetrahydropyranyl rings of the C3-C19 component (3). The stereocontrolled asymmetric allylation process is also used for development of the C28-C41 fragment (4). Novel Barbier coupling reactions of alpha-iodomethyl oxazoles and related thiazoles are described with samarium iodide. The convergent assembly of components 4 and 5 features formation of the fully substituted C22-C26 pyran by intramolecular capture of an allyl cation intermediate with high facial selectivity, and further efforts lead to E-C19/C20 olefination. The synthesis culminates with use of a modified Julia olefination for attachment of the C42-C46 segment and subsequent late-stage macrocyclization by installation of the (Z)-C2/C3 alpha,beta-unsaturated lactone.
