RESUMO
Here we report the discovery and optimization of a series of bivalent bromodomain and extraterminal inhibitors. Starting with the observation of BRD4 activity of compounds from a previous program, the compounds were optimized for BRD4 potency and physical properties. The optimized compound from this campaign exhibited excellent pharmacokinetic profile and exhibited high potency in vitro and in vivo effecting c-Myc downregulation and tumor growth inhibition in xenograft studies. This compound was selected as the development candidate, AZD5153. The series showed enhanced potency as a result of bivalent binding and a clear correlation between BRD4 activity and cellular potency.
Assuntos
Antineoplásicos/química , Compostos Heterocíclicos com 2 Anéis/química , Proteínas Nucleares/antagonistas & inibidores , Piperazinas/química , Fatores de Transcrição/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Células CACO-2 , Proteínas de Ciclo Celular , Cristalografia por Raios X , Cães , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Compostos Heterocíclicos com 2 Anéis/farmacologia , Xenoenxertos , Humanos , Camundongos SCID , Transplante de Neoplasias , Piperazinas/farmacocinética , Piperazinas/farmacologia , Conformação Proteica , Pirazóis , Piridazinas , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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
Continued androgen receptor (AR) expression and signaling is a key driver in castration-resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed, and therefore remains a target for the treatment of progressive disease. Here, we describe the biological characterization of AZD3514, an orally bioavailable drug that inhibits androgen-dependent and -independent AR signaling. AZD3514 modulates AR signaling through two distinct mechanisms, an inhibition of ligand-driven nuclear translocation of AR and a downregulation of receptor levels, both of which were observed in vitro and in vivo. AZD3514 inhibited testosterone-driven seminal vesicle development in juvenile male rats and the growth of androgen-dependent Dunning R3327H prostate tumors in adult rats. Furthermore, this class of compound showed antitumor activity in the HID28 mouse model of CRPC in vivo. AZD3514 is currently in phase I clinical evaluation.
Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Antineoplásicos/farmacologia , Neoplasias de Próstata Resistentes à Castração/patologia , Piridazinas/farmacologia , Receptores Androgênicos/metabolismo , Glândulas Seminais/efeitos dos fármacos , Acetato de Abiraterona , Antagonistas de Receptores de Andrógenos/metabolismo , Androstadienos/farmacologia , Animais , Antineoplásicos/metabolismo , Benzamidas , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação para Baixo , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Masculino , Camundongos , Camundongos Nus , Nitrilas , Feniltioidantoína/análogos & derivados , Feniltioidantoína/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Piridazinas/síntese química , Piridazinas/metabolismo , Ratos , Ratos Wistar , Receptores Androgênicos/genética , Glândulas Seminais/crescimento & desenvolvimento , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Removal of the basic piperazine nitrogen atom, introduction of a solubilising end group and partial reduction of the triazolopyridazine moiety in the previously-described lead androgen receptor downregulator 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (1) addressed hERG and physical property issues, and led to clinical candidate 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (12), designated AZD3514, that is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.
Assuntos
Regulação para Baixo/efeitos dos fármacos , Descoberta de Drogas , Neoplasias da Próstata/tratamento farmacológico , Piridazinas/farmacologia , Receptores Androgênicos/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Estrutura Molecular , Neoplasias da Próstata/patologia , Piridazinas/síntese química , Piridazinas/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
We disclose a novel series of insulin-like growth factor-1 receptor kinase inhibitors based on the 3-(pyrimidin-4-yl)-imidazo[1,2-a]pyridine scaffold. The influence on the inhibitory activity of substitution on the imidazopyridine and at the C5 position of the pyrimidine is discussed. In the course of this optimization, we discovered a potent and selective inhibitor with suitable pharmacokinetics for oral administration.
Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Cães , Humanos , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
Chemical starting points were investigated for downregulation of the androgen receptor as an approach to treatment of advanced prostate cancer. Although prototypic steroidal downregulators such as 6a designed for intramuscular administration showed insufficient cellular potency, a medicinal chemistry program derived from a novel androgen receptor ligand 8a led to 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (10b), for which high plasma levels following oral administration in a preclinical model compensate for moderate cellular potency.
Assuntos
Neoplasias da Próstata/tratamento farmacológico , Piridazinas/farmacologia , Receptores Androgênicos/metabolismo , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Humanos , Ligantes , Masculino , Modelos Moleculares , Estrutura Molecular , Peso Molecular , Neoplasias da Próstata/metabolismo , Piridazinas/síntese química , Piridazinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Insights from cell cycle research have led to the hypothesis that tumors may be selectively sensitized to DNA-damaging agents resulting in improved antitumor activity and a wider therapeutic margin. The theory relies on the observation that the majority of tumors are deficient in the G1-DNA damage checkpoint pathway resulting in reliance on S and G2 checkpoints for DNA repair and cell survival. The S and G2 checkpoints are regulated by checkpoint kinase 1, a serine/threonine kinase that is activated in response to DNA damage; thus, inhibition of checkpoint kinase 1 signaling impairs DNA repair and increases tumor cell death. Normal tissues, however, have a functioning G1 checkpoint signaling pathway allowing for DNA repair and cell survival. Here, we describe the preclinical profile of AZD7762, a potent ATP-competitive checkpoint kinase inhibitor in clinical trials. AZD7762 has been profiled extensively in vitro and in vivo in combination with DNA-damaging agents and has been shown to potentiate response in several different settings where inhibition of checkpoint kinase results in the abrogation of DNA damage-induced cell cycle arrest. Dose-dependent potentiation of antitumor activity, when AZD7762 is administered in combination with DNA-damaging agents, has been observed in multiple xenograft models with several DNA-damaging agents, further supporting the potential of checkpoint kinase inhibitors to enhance the efficacy of both conventional chemotherapy and radiotherapy and increase patient response rates in a variety of settings.