RESUMO
Fulvestrant is an estrogen receptor (ER) antagonist administered to breast cancer patients by monthly intramuscular injection. Given its present limitations of dosing and route of administration, a more flexible orally available compound has been sought to pursue the potential benefits of this drug in patients with advanced metastatic disease. Here we report the identification and characterization of AZD9496, a nonsteroidal small-molecule inhibitor of ERα, which is a potent and selective antagonist and downregulator of ERα in vitro and in vivo in ER-positive models of breast cancer. Significant tumor growth inhibition was observed as low as 0.5 mg/kg dose in the estrogen-dependent MCF-7 xenograft model, where this effect was accompanied by a dose-dependent decrease in PR protein levels, demonstrating potent antagonist activity. Combining AZD9496 with PI3K pathway and CDK4/6 inhibitors led to further growth-inhibitory effects compared with monotherapy alone. Tumor regressions were also seen in a long-term estrogen-deprived breast model, where significant downregulation of ERα protein was observed. AZD9496 bound and downregulated clinically relevant ESR1 mutants in vitro and inhibited tumor growth in an ESR1-mutant patient-derived xenograft model that included a D538G mutation. Collectively, the pharmacologic evidence showed that AZD9496 is an oral, nonsteroidal, selective estrogen receptor antagonist and downregulator in ER(+) breast cells that could provide meaningful benefit to ER(+) breast cancer patients. AZD9496 is currently being evaluated in a phase I clinical trial. Cancer Res; 76(11); 3307-18. ©2016 AACR.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Cinamatos/farmacologia , Moduladores de Receptor Estrogênico/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/genética , Indóis/farmacologia , Mutação/genética , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Cinamatos/administração & dosagem , Avaliação Pré-Clínica de Medicamentos , Moduladores de Receptor Estrogênico/administração & dosagem , Receptor alfa de Estrogênio/química , Feminino , Humanos , Indóis/administração & dosagem , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Conformação Proteica , Ratos , Células Tumorais Cultivadas , Útero/metabolismo , Útero/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The discovery of an orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described. A directed screen identified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided by crystal structures of novel ligands bound to an ER construct, medicinal chemistry iterations led to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (30b, AZD9496), a clinical candidate with high oral bioavailability across preclinical species that is currently being evaluated in phase I clinical trials for the treatment of advanced estrogen receptor (ER) positive breast cancer.
Assuntos
Antineoplásicos/metabolismo , Cinamatos/química , Cinamatos/metabolismo , Antagonistas de Estrogênios/síntese química , Antagonistas de Estrogênios/farmacologia , Moduladores de Receptor Estrogênico/síntese química , Moduladores de Receptor Estrogênico/farmacologia , Indóis/química , Indóis/metabolismo , Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios Clínicos Fase I como Assunto , Regulação para Baixo/efeitos dos fármacos , Desenho de Fármacos , Feminino , Humanos , Injeções Intramusculares , Difração de Raios XRESUMO
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.
Assuntos
Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Administração Oral , Animais , Linhagem Celular , Espectroscopia de Ressonância Magnética , Camundongos , Transplante de Neoplasias , Fosforilação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Quinazolinas/administração & dosagem , Quinazolinas/química , Quinazolinas/farmacocinética , Relação Estrutura-AtividadeRESUMO
Neutral 5-substituted 4-anilinoquinazolines addressed high in vivo clearance and phospholipidosis associated with previous basic compounds. A representative compound 8a inhibited tumor growth in a mouse xenograft model when co-administered with the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT), and data are consistent with pharmacology primarily reflecting inhibition of erbB2 receptor tyrosine kinase.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Quinazolinas/química , Quinazolinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Administração Oral , Compostos de Anilina/química , Animais , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica , Proliferação de Células/efeitos dos fármacos , Cães , Sinergismo Farmacológico , Camundongos , Estrutura Molecular , Quinazolinas/farmacocinética , Ratos , Triazóis/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The structure-activity and structure-property relationships of anilinoquinazoline inhibitors of EGFR were investigated. Strategies to lower volume of distribution and shorten half-life through structure and pKa modulation are discussed.