ABSTRACT
More than 75% of breast cancers are estrogen receptor alpha (ERα) positive (ER+), and resistance to current hormone therapies occurs in one-third of ER+ patients. Tumor resistance is still ERα-dependent, but mutations usually confer constitutive activation to the hormone receptor, rendering ERα modulator drugs such as tamoxifen and aromatase inhibitors ineffective. Fulvestrant is a potent selective estrogen receptor degrader (SERD), which degrades the ERα receptor in drug-resistant tumors and has been approved for the treatment of hormone-receptor-positive metastatic breast cancer following antiestrogen therapy. However, fulvestrant shows poor pharmacokinetic properties in human, low solubility, weak permeation, and high metabolism, limiting its administration to inconvenient intramuscular injections. This Drug Annotation describes the identification and optimization of a new series of potent orally available SERDs, which led to the discovery of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (43d), showing promising antitumor activity in breast cancer mice xenograft models and whose properties warranted clinical evaluation.
Subject(s)
Breast Neoplasms/drug therapy , Drug Discovery/methods , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Receptors, Estrogen/metabolism , Selective Estrogen Receptor Modulators/therapeutic use , Animals , Breast Neoplasms/metabolism , Crystallography, X-Ray , Dogs , Drug Resistance, Neoplasm , Female , Half-Life , High-Throughput Screening Assays , Humans , Ligands , Mice , Models, Molecular , Rats , Receptors, Estrogen/drug effects , Selective Estrogen Receptor Modulators/pharmacokinetics , Selective Estrogen Receptor Modulators/pharmacology , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this lipid kinase in cancer maintenance and progression. Herein, we report the discovery of a series of tetrahydropyrimidopyrimidinone derivatives. Starting with hit compound 1a, medicinal chemistry optimization led to compound 31. This molecule displays potent activity, an exquisite selectivity for Vps34 with excellent properties. The X-ray crystal structure of compound 31 in human Vps34 illustrates how the unique molecular features of the morpholine synthon bestows selectivity against class I PI3Ks. This molecule exhibits suitable in vivo mouse PK parameters and induces a sustained inhibition of Vps34 upon acute administration. Compound 31 constitutes an optimized Vps34 inhibitor that could be used to investigate human cancer biology.
Subject(s)
Antineoplastic Agents/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Class III Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Neoplasms/drug therapy , Pyrimidinones/pharmacology , Amino Acid Sequence , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Area Under Curve , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Caco-2 Cells , Cell Line, Tumor , Class III Phosphatidylinositol 3-Kinases/chemistry , Class III Phosphatidylinositol 3-Kinases/metabolism , Crystallography, X-Ray , Drug Discovery , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , HeLa Cells , Humans , Male , Mice, SCID , Models, Chemical , Models, Molecular , Molecular Sequence Data , Molecular Structure , Neoplasms/pathology , Protein Binding , Protein Structure, Tertiary , Pyrimidinones/chemistry , Pyrimidinones/pharmacokinetics , Rats, Sprague-Dawley , Sequence Homology, Amino Acid , Thermodynamics , 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
We exploit the concept of using hydrogen bonds to link multiple ligands for maintaining simultaneous interactions with polyvalent binding sites. This approach is demonstrated by the syntheses and evaluation of pseudo-bivalent ligands as potent inhibitors of human beta-tryptase.
