ABSTRACT
As part of our investigation into pyrazolo[1,5-a]pyridines as novel p110α selective PI3 kinase inhibitors, we report a range of analogues with improved aqueous solubility by the addition of a basic amine. The compounds demonstrated comparable p110α potency and selectivity to earlier compounds but with up to 1000× greater aqueous solubility, as the hydrochloride salts. The compounds also displayed good activity in a cellular assay of PI3 kinase activity.
Subject(s)
Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyridines/pharmacology , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Hydrazones/chemical synthesis , Hydrazones/pharmacology , Hydrazones/toxicity , Mice , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/toxicity , Pyrazoles/chemical synthesis , Pyrazoles/toxicity , Pyridines/chemical synthesis , Pyridines/toxicity , SolubilityABSTRACT
A novel series of TGX-221 analogues was prepared and tested for their potency against the p110α, p110ß, and p110δ isoforms of the PI3K enzyme, and in two cellular assays. The biological results were interpreted in terms of a p110ß comparative model, in order to account for their selectivity towards this isoform. A CH2NH type linker is proposed to allow binding into the specificity pocket proposed to accommodate the high p110ß-selectivity of TGX-221, although there was limited steric tolerance for substituents on the pendant ring with the 2-position most favourable for substitution.
Subject(s)
Antineoplastic Agents/pharmacology , Morpholines/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Protein Subunits/antagonists & inhibitors , Pyrimidinones/pharmacology , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Cell Survival/drug effects , Class Ia Phosphatidylinositol 3-Kinase/chemistry , Class Ia Phosphatidylinositol 3-Kinase/metabolism , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Morpholines/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Protein Subunits/chemistry , Protein Subunits/metabolism , Pyrimidinones/chemical synthesis , Structure-Activity RelationshipABSTRACT
A range of 4-substituted derivatives of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) were prepared in a search for more soluble analogs. 4-Aminoalkoxy substituents provided the most potent derivatives, with the 4-O(CH2)3NMe2 analog (compound 14) being identified as displaying the best overall activity in combination with good aqueous solubility (25 mg/mL for the hydrochloride salt). This compound was tested in a U87MG xenograft model, but displayed less potency than ZSTK474 as a result of an unfavorable pharmacokinetic profile.
Subject(s)
Antineoplastic Agents/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Triazines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , HCT116 Cells , Homeodomain Proteins/metabolism , Humans , Male , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Structure , Phosphatidylinositol 3-Kinases/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Signal Transduction/drug effects , Solubility , Structure-Activity Relationship , Triazines/chemical synthesis , Triazines/chemistryABSTRACT
We have made a novel series of pyrazolo[1,5-a]pyridines as PI3 kinase inhibitors, and demonstrated their selectivity for the p110α isoform over the other Class Ia PI3 kinases. We investigated the SAR around the pyrazolo[1,5-a]pyridine ring system, and found compound 5x to be a particularly potent example (p110α IC(50) 0.9nM). This compound inhibits cell proliferation and phosphorylation of Akt/PKB, a downstream marker of PI3 kinase activity, and showed in vivo activity in an HCT-116 human xenograft model.
Subject(s)
Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemistry , Pyridines/chemistry , 3-Phosphoinositide-Dependent Protein Kinases , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Binding Sites , Cell Line, Tumor , Computer Simulation , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Humans , Mice , Neoplasms/drug therapy , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/metabolism , Pyridines/chemical synthesis , Pyridines/pharmacology , Transplantation, HeterologousABSTRACT
Structure-activity relationship studies of the pyrazolo[1,5-a]pyridine class of PI3 kinase inhibitors show that substitution off the hydrazone nitrogen and replacement of the sulfonyl both gave a loss of p110α selectivity, with the exception of an N-hydroxyethyl analogue. Limited substitutions were tolerated around the phenyl ring; in particular the 2,5-substitution pattern was important for PI3 kinase activity. The N-hydroxyethyl compound also showed good inhibition of cell proliferation and inhibition of phosphorylation of Akt/PKB, a downstream marker of PI3 kinase activity. It had suitable pharmacokinetics for evaluation in vivo, and showed tumour growth inhibition in two human tumour cell lines in xenograft studies. This work has provided suggestions for the design of more soluble analogues.
