ABSTRACT
The Aurora family of serine/threonine kinases is essential for mitosis. Their crucial role in cell cycle regulation and aberrant expression in a broad range of malignancies have been demonstrated and have prompted intensive search for small molecule Aurora inhibitors. Indeed, over 10 of them have reached the clinic as potential anticancer therapies. We report herein the discovery and optimization of a novel series of tricyclic molecules that has led to SAR156497, an exquisitely selective Aurora A, B, and C inhibitor with in vitro and in vivo efficacy. We also provide insights into its mode of binding to its target proteins, which could explain its selectivity.
Subject(s)
Antineoplastic Agents/pharmacology , Aurora Kinases/antagonists & inhibitors , Benzimidazoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Quinolones/pharmacology , Small Molecule Libraries/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Aurora Kinase A/antagonists & inhibitors , Aurora Kinase A/chemistry , Aurora Kinase A/metabolism , Aurora Kinase B/antagonists & inhibitors , Aurora Kinase B/chemistry , Aurora Kinase B/metabolism , Aurora Kinase C/antagonists & inhibitors , Aurora Kinase C/chemistry , Aurora Kinase C/metabolism , Aurora Kinases/chemistry , Aurora Kinases/metabolism , Benzimidazoles/chemistry , Benzimidazoles/metabolism , Female , HCT116 Cells , Humans , Mice, SCID , Models, Chemical , Models, Molecular , Molecular Structure , Neoplasms/drug therapy , Neoplasms/pathology , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Structure, Tertiary , Quinolones/chemistry , Quinolones/metabolism , Sf9 Cells , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Compelling molecular biology publications have reported the implication of phosphoinositide kinase PI3Kß in PTEN-deficient cell line growth and proliferation. These findings supported a scientific rationale for the development of PI3Kß-specific inhibitors for the treatment of PTEN-deficient cancers. This paper describes the discovery of 2-[2-(2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (7) and the optimization of this new series of active and selective pyrimidone indoline amide PI3Kß inhibitors. 2-[2-(2-Methyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (28), identified following a carefully designed methyl scan, displayed improved physicochemical and in vitro pharmacokinetic properties. Structural biology efforts enabled the acquisition of the first X-ray cocrystal structure of p110ß with the selective inhibitor compound 28 bound to the ATP site. The nonplanar binding mode described herein is consistent with observed structure-activity relationship for the series. Compound 28 demonstrated significant in vivo activity in a UACC-62 xenograft model in mice, warranting further preclinical investigation. Following successful development, compound 28 entered phase I/Ib clinical trial in patients with advanced cancer.
Subject(s)
Antineoplastic Agents/chemistry , Indoles/chemistry , Neoplasms/drug therapy , PTEN Phosphohydrolase/deficiency , Phosphoinositide-3 Kinase Inhibitors , Pyrimidinones/chemistry , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Biological Availability , Cell Line, Tumor , Cell Membrane Permeability , Crystallography, X-Ray , Dogs , Drug Screening Assays, Antitumor , Female , Heterografts , Humans , Indoles/pharmacokinetics , Indoles/pharmacology , Male , Mice , Mice, Inbred BALB C , Mice, SCID , Microsomes, Liver/metabolism , Molecular Conformation , Molecular Docking Simulation , Neoplasm Transplantation , Neoplasms/enzymology , PTEN Phosphohydrolase/genetics , Protein Binding , Pyrimidinones/pharmacokinetics , Pyrimidinones/pharmacology , Rats , Rats, Nude , Solubility , Stereoisomerism , Structure-Activity RelationshipABSTRACT
From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kß isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kß. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line. Optimization of in vitro pharmocokinetic properties led to compound 25 exhibiting 52% bioavailability in mice and target engagement in an acute PK/PD study.
