ABSTRACT
Starting from potent inhibitors of PI3Kα having poor general kinase selectivity (e.g., 1 and 2), optimisation of this series led to the identification of 25, a potent inhibitor of PI3Kα (wild type, E545K and H1047R mutations) and PI3Kδ, selective versus PI3Kß and PI3Kγ, with excellent general kinase selectivity. Compound 25 displayed low metabolic turnover and suitable physical properties for oral administration. In vivo, compound 25 showed pharmacodynamic modulation of AKT phosphorylation and near complete inhibition of tumour growth (93% tumour growth inhibition) in a murine H1047R PI3Kα mutated SKOV-3 xenograft tumour model after chronic oral administration at 25mg/kg b.i.d. Compound 25, also known as AZD8835, is currently in phase I clinical trials.
Subject(s)
Antineoplastic Agents/pharmacology , Oxadiazoles/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Piperidines/pharmacology , Protein Kinase Inhibitors/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Dogs , Humans , Mice , Mice, Nude , Mice, SCID , Molecular Docking Simulation , Oxadiazoles/chemical synthesis , Piperidines/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Rats , Xenograft Model Antitumor AssaysABSTRACT
Several studies have highlighted the dependency of PTEN deficient tumors to PI3Kß activity and specific inhibition of PI3Kδ has been shown activity against human B-cell cancers. We describe the discovery and optimization of a series of 8-(1-anilino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamides as PI3Kß/δ inhibitors, which led to the discovery of the clinical candidate 13, also known as AZD8186. On the basis of the lower lipophilicity of the chromen-4-one core compared to the previously utilized pyrido[1,2-a]pyrimid-4-one core, this series of compounds displayed high metabolic stability and suitable physical properties for oral administration. Compound 13 showed profound pharmacodynamic modulation of p-Akt in PTEN-deficient PC3 prostate tumor bearing mice after oral administration and showed complete inhibition of tumor growth in the mouse PTEN-deficient PC3 prostate tumor xenograft model. 13 was selected as a clinical candidate for treatment of PTEN-deficient cancers and has recently entered phase I clinical trials.
Subject(s)
Aniline Compounds/chemical synthesis , Chromones/chemical synthesis , Neoplasms, Experimental/drug therapy , PTEN Phosphohydrolase/deficiency , Phosphoinositide-3 Kinase Inhibitors , Aniline Compounds/pharmacology , Animals , Chromones/pharmacology , Dogs , Drug Discovery , Humans , Male , Mice , Neoplasms, Experimental/chemistry , Structure-Activity RelationshipABSTRACT
Potent antagonists of the integrin α(5)ß(1), which are RGD mimetics built from tyrosine are described. This letter describes the optimization of in vitro potency obtained by variation of two parts of the molecule, the basic group and the linker between the basic group and the phenyl central core.
Subject(s)
Integrin alpha5beta1/antagonists & inhibitors , Oligopeptides/chemical synthesis , Tyrosine/analogs & derivatives , Tyrosine/chemical synthesis , Cell Adhesion/drug effects , Cell Survival/drug effects , Fibrinogen/chemistry , Fibronectins/chemistry , Humans , Integrin alpha5beta1/metabolism , K562 Cells , Models, Molecular , Molecular Mimicry , Oligopeptides/pharmacology , Serum Albumin/chemistry , Structure-Activity Relationship , Tyrosine/pharmacologyABSTRACT
Potent antagonists of the integrin α(5)ß(1), which are RGD mimetics built from tyrosine are described. This paper describes the optimization of in vitro potency obtained by variation of two parts of the molecule, the central aromatic core and the amide moiety.
Subject(s)
Integrin alpha5beta1/antagonists & inhibitors , Oligopeptides/chemical synthesis , Tyrosine/analogs & derivatives , Tyrosine/chemical synthesis , Cell Adhesion/drug effects , Cell Survival/drug effects , Fibrinogen/chemistry , Fibronectins/chemistry , Humans , Integrin alpha5beta1/metabolism , K562 Cells , Models, Molecular , Molecular Mimicry , Oligopeptides/pharmacology , Serum Albumin/chemistry , Structure-Activity Relationship , Tyrosine/pharmacologyABSTRACT
We have identified a new series of C-5 substituted indazolylaminoquinazolines as potent erbB2 kinase inhibitors. The lead compound 22 showed excellent in vitro potency, good physical properties, acceptable oral pharmacokinetics in rat and dog, and low human in vitro clearance. It showed at least equivalent activity dose for dose compared to lapatinib in various erbB2- or EGFR-driven xenograft models after chronic oral administration.
Subject(s)
Antineoplastic Agents/pharmacology , ErbB Receptors/antagonists & inhibitors , Indazoles/pharmacology , Neoplasms, Experimental/drug therapy , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Dogs , Epidermal Growth Factor/pharmacology , Ether-A-Go-Go Potassium Channels , Female , Hepatocytes/cytology , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Indazoles/chemical synthesis , Keratinocytes/cytology , Keratinocytes/drug effects , Keratinocytes/metabolism , Lapatinib , Male , Metabolic Clearance Rate , Mice , Mice, Nude , Mice, SCID , Microsomes/drug effects , Molecular Structure , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemical synthesis , Quinazolines/chemical synthesis , Rats , Rats, Wistar , Survival Rate , Xenograft Model Antitumor AssaysABSTRACT
Starting from initial lead 1 containing a basic 5-substituent, optimisation of the glycolamide-derived neutral 5-substituent led to potent inhibitors of erbB2 with good pharmacokinetics. Representative compounds 19 and 21 inhibited phosphorylation of erbB2 in a mouse BT474C xenograft model after oral administration.
Subject(s)
Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Administration, Oral , Animals , Cell Line , Magnetic Resonance Spectroscopy , Mice , Neoplasm Transplantation , Phosphorylation , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Quinazolines/administration & dosage , Quinazolines/chemistry , Quinazolines/pharmacokinetics , Structure-Activity RelationshipABSTRACT
A series of 5,7-disubstituted quinazolines, bearing 4-heteroaryl substituents such as 2-pyridinylamine or 2-pyrazinylamine, has been synthetised and evaluated as c-Src kinase inhibitors. Highly potent inhibition, high selectivity and physical properties suitable for oral dosing were achieved within this series: 23d and 42 were identified as sub-0.1muM inhibitors in a c-Src-driven cell proliferation assay and displayed adequate rat pharmacokinetics after oral administration.
