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1.
Br J Pharmacol ; 178(3): 600-613, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33125717

RESUMO

BACKGROUND AND PURPOSE: Savolitinib (AZD6094, HMPL-504, volitinib) is an oral, potent, and highly MET receptor TK inhibitor. This series of studies aimed to develop a pharmacokinetic-pharmacodynamic (PK/PD) model to link inhibition of MET phosphorylation (pMET) by savolitinib with anti-tumour activity. EXPERIMENTAL APPROACH: Cell line-derived xenograft (CDX) experiments using human lung cancer (EBC-1) and gastric cancer (MKN-45) cells were conducted in athymic nude mice using a variety of doses and schedules of savolitinib. Tumour pMET changes and growth inhibition were calculated after 28 days. Population PK/PD techniques were used to construct a PK/PD model for savolitinib. KEY RESULTS: Savolitinib showed dose- and dose frequency-dependent anti-tumour activity in the CDX models, with more frequent, lower dosing schedules (e.g., twice daily) being more effective than intermittent, higher dosing schedules (e.g., 4 days on/3 days off or 2 days on/5 days off). There was a clear exposure-response relationship, with maximal suppression of pMET of >90%. Data from additional CDX and patient-derived xenograft (PDX) models overlapped, allowing calculation of a single EC50 of 0.38 ng·ml-1 . Tumour growth modelling demonstrated that prolonged, high levels of pMET inhibition (>90%) were required for tumour stasis and regression in the models. CONCLUSION AND IMPLICATIONS: High and persistent levels of MET inhibition by savolitinib were needed for optimal monotherapy anti-tumour activity in preclinical models. The modelling framework developed here can be used to translate tumour growth inhibition from the mouse to human and thus guide choice of clinical dose and schedule.


Assuntos
Antineoplásicos , Proteínas Proto-Oncogênicas c-met , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Camundongos , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Pirazinas , Triazinas , Ensaios Antitumorais Modelo de Xenoenxerto
2.
PLoS One ; 13(7): e0200826, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30036377

RESUMO

BRD4 is a transcriptional co-activator functioning to recruit regulatory complexes to acetylated chromatin. A subset of High-grade Serous Ovarian Cancer (HGSOC) patients are typified by focal, recurrent BRD4 gene amplifications. Despite previously described cancer dependencies, it is unclear whether BRD4 amplification events are oncogenic in HGSOC. We find that physiologically relevant levels of expression of BRD4 isoforms in non-transformed ovarian cells result in cellular transformation. Transcriptional profiling of BRD4-transformed ovarian cells, and BRD4-amplified HGSOC patient samples revealed shared expression patterns, including enriched MYC, and E2F1 gene signatures. Furthermore, we demonstrate that a novel BET inhibitor, AZD5153, is highly active in BRD4-amplified patient derived xenografts and uncover Neuregulin-1 as a novel BRD4 effector. Experiments involving Neuregulin-1 inhibition and exogenous addition, demonstrate Neuregulin-1 as necessary and sufficient for BRD4-mediated transformation. This study demonstrates the oncogenic potential of BRD4 amplification in cancer and establishes BRD4-amplified HGSOC as a potential patient population that could benefit from BET inhibitors.


Assuntos
Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica , Compostos Heterocíclicos com 2 Anéis/farmacologia , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Piperazinas/farmacologia , Fatores de Transcrição/genética , Algoritmos , Animais , Carcinogênese/genética , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Cistadenocarcinoma Seroso/genética , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Camundongos , Transplante de Neoplasias , Neuregulina-1/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Proteínas/genética , Proteínas/metabolismo , Pirazóis , Piridazinas , Transdução de Sinais , Fatores de Transcrição/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Oncotarget ; 7(36): 57651-57670, 2016 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-27472392

RESUMO

Lung cancer is the most common cause of cancer death globally with a significant, unmet need for more efficacious treatments. The receptor tyrosine kinase MET has been implicated as an oncogene in numerous cancer subtypes, including non-small cell lung cancer (NSCLC). Here we explore the therapeutic potential of savolitinib (volitinib, AZD6094, HMPL-504), a potent and selective MET inhibitor, in NSCLC. In vitro, savolitinib inhibits MET phosphorylation with nanomolar potency, which correlates with blockade of PI3K/AKT and MAPK signaling as well as MYC down-regulation. In vivo, savolitinib causes inhibition of these pathways and significantly decreases growth of MET-dependent xenografts. To understand resistance mechanisms, we generated savolitinib resistance in MET-amplified NSCLC cell lines and analyzed individual clones. We found that upregulation of MYC and constitutive mTOR pathway activation is a conserved feature of resistant clones that can be overcome by knockdown of MYC or dual mTORC1/2 inhibition. Lastly, we demonstrate that mechanisms of resistance are heterogeneous, arising via a switch to EGFR dependence or by a requirement for PIM signaling. This work demonstrates the efficacy of savolitinib in NSCLC and characterizes acquired resistance, identifying both known and novel mechanisms that may inform combination strategies in the clinic.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas c-myc/metabolismo , Pirazinas/química , Serina-Treonina Quinases TOR/metabolismo , Triazinas/química , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Regulação para Baixo , Receptores ErbB/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-met/metabolismo
4.
Mol Cancer Ther ; 15(11): 2563-2574, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27573426

RESUMO

The bromodomain and extraterminal (BET) protein BRD4 regulates gene expression via recruitment of transcriptional regulatory complexes to acetylated chromatin. Pharmacological targeting of BRD4 bromodomains by small molecule inhibitors has proven to be an effective means to disrupt aberrant transcriptional programs critical for tumor growth and/or survival. Herein, we report AZD5153, a potent, selective, and orally available BET/BRD4 bromodomain inhibitor possessing a bivalent binding mode. Unlike previously described monovalent inhibitors, AZD5153 ligates two bromodomains in BRD4 simultaneously. The enhanced avidity afforded through bivalent binding translates into increased cellular and antitumor activity in preclinical hematologic tumor models. In vivo administration of AZD5153 led to tumor stasis or regression in multiple xenograft models of acute myeloid leukemia, multiple myeloma, and diffuse large B-cell lymphoma. The relationship between AZD5153 exposure and efficacy suggests that prolonged BRD4 target coverage is a primary efficacy driver. AZD5153 treatment markedly affects transcriptional programs of MYC, E2F, and mTOR. Of note, mTOR pathway modulation is associated with cell line sensitivity to AZD5153. Transcriptional modulation of MYC and HEXIM1 was confirmed in AZD5153-treated human whole blood, thus supporting their use as clinical pharmacodynamic biomarkers. This study establishes AZD5153 as a highly potent, orally available BET/BRD4 inhibitor and provides a rationale for clinical development in hematologic malignancies. Mol Cancer Ther; 15(11); 2563-74. ©2016 AACR.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Hematológicas/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Biomarcadores , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fatores de Transcrição E2F/genética , Fatores de Transcrição E2F/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Camundongos , Terapia de Alvo Molecular , Proteínas Nucleares/química , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/química , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Med Chem ; 58(17): 7057-75, 2015 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-26291341

RESUMO

We report here a novel series of benzimidazole sulfonamides that act as antagonists of the S1P1 receptor, identified by exploiting an understanding of the pharmacophore of a high throughput screening (HTS)-derived series of compounds described previously. Lead compound 2 potently inhibits S1P-induced receptor internalization in a cell-based assay (EC50 = 0.05 µM), but has poor physical properties and metabolic stability. Evolution of this compound through structure-activity relationship development and property optimization led to in vivo probes such as 4. However, this compound was unexpectedly found to be a potent CYP3A inducer in human hepatocytes, and thus further chemistry efforts were directed at addressing this liability. By employing a pregnane X receptor (PXR) reporter gene assay to prioritize compounds for further testing in human hepatocytes, we identified lipophilicity as a key molecular property influencing the likelihood of P450 induction. Ultimately, we have identified compounds such as 46 and 47, which demonstrate the desired S1P1 antagonist activity while having greatly reduced risk of CYP3A induction in humans. These compounds have excellent oral bioavailability in preclinical species and exhibit pharmacodynamic effects of S1P1 antagonism in several in vivo models following oral dosing. Relatively modest antitumor activity was observed in multiple xenograft models, however, suggesting that selective S1P1 antagonists would have limited utility as anticancer therapeutics as single agents.


Assuntos
Benzimidazóis/química , Piridinas/química , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Sulfonamidas/química , Administração Oral , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Disponibilidade Biológica , Células Cultivadas , Citocromo P-450 CYP3A/biossíntese , Indutores do Citocromo P-450 CYP3A/síntese química , Indutores do Citocromo P-450 CYP3A/química , Indutores do Citocromo P-450 CYP3A/farmacologia , Genes Reporter , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Receptor de Pregnano X , Piridinas/síntese química , Piridinas/farmacologia , Receptores de Esteroides/genética , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Mol Cancer Ther ; 14(1): 48-58, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25398829

RESUMO

Loss of PTEN protein results in upregulation of the PI3K/AKT pathway, which appears dependent on the PI3Kß isoform. Inhibitors of PI3Kß have potential to reduce growth of tumors in which loss of PTEN drives tumor progression. We have developed a small-molecule inhibitor of PI3Kß and PI3Kδ (AZD8186) and assessed its antitumor activity across a panel of cell lines. We have then explored the antitumor effects as single agent and in combination with docetaxel in triple-negative breast (TNBC) and prostate cancer models. In vitro, AZD8186 inhibited growth of a range of cell lines. Sensitivity was associated with inhibition of the AKT pathway. Cells sensitive to AZD8186 (GI50 < 1 µmol/L) are enriched for, but not exclusively associated with, PTEN deficiency. In vivo, AZD8186 inhibits PI3K pathway biomarkers in prostate and TNBC tumors. Scheduling treatment with AZD8186 shows antitumor activity required only intermittent exposure, and that increased tumor control is achieved when AZD8186 is used in combination with docetaxel. AZD8186 is a potent inhibitor of PI3Kß with activity against PI3Kδ signaling, and has potential to reduce growth of tumors dependent on dysregulated PTEN for growth. Moreover, AZD8186 can be combined with docetaxel, a chemotherapy commonly used to treat advanced TBNC and prostate tumors. The ability to schedule AZD8186 and maintain efficacy offers opportunity to combine AZD8186 more effectively with other drugs.


Assuntos
Compostos de Anilina/administração & dosagem , Antineoplásicos/administração & dosagem , Cromonas/administração & dosagem , Inibidores de Fosfoinositídeo-3 Quinase , Neoplasias da Próstata/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Taxoides/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromonas/farmacologia , Docetaxel , Sinergismo Farmacológico , Feminino , Humanos , Masculino , Camundongos , PTEN Fosfo-Hidrolase/deficiência , Neoplasias da Próstata/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Med Chem ; 56(24): 9897-919, 2013 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-24320998

RESUMO

A series of dimeric compounds based on the AVPI motif of Smac were designed and prepared as antagonists of the inhibitor of apoptosis proteins (IAPs). Optimization of cellular potency, physical properties, and pharmacokinetic parameters led to the identification of compound 14 (AZD5582), which binds potently to the BIR3 domains of cIAP1, cIAP2, and XIAP (IC50 = 15, 21, and 15 nM, respectively). This compound causes cIAP1 degradation and induces apoptosis in the MDA-MB-231 breast cancer cell line at subnanomolar concentrations in vitro. When administered intravenously to MDA-MB-231 xenograft-bearing mice, 14 results in cIAP1 degradation and caspase-3 cleavage within tumor cells and causes substantial tumor regressions following two weekly doses of 3.0 mg/kg. Antiproliferative effects are observed with 14 in only a small subset of the over 200 cancer cell lines examined, consistent with other published IAP inhibitors. As a result of its in vitro and in vivo profile, 14 was nominated as a candidate for clinical development.


Assuntos
Alcinos/farmacologia , Antineoplásicos/farmacologia , Materiais Biomiméticos/farmacologia , Descoberta de Drogas , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Oligopeptídeos/farmacologia , Alcinos/síntese química , Alcinos/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dimerização , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Camundongos , Conformação Molecular , Neoplasias/patologia , Oligopeptídeos/síntese química , Oligopeptídeos/química , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Med Chem ; 54(19): 6734-50, 2011 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-21899292

RESUMO

Structure-activity relationship analysis identified (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), from a series of novel kinesin spindle protein (KSP) inhibitors, as exhibiting both excellent biochemical potency and pharmaceutical properties suitable for clinical development. The selected compound arrested cells in mitosis leading to the formation of the monopolar spindle phenotype characteristic of KSP inhibition and induction of cellular death. A favorable pharmacokinetic profile and notable in vivo efficacy supported the selection of this compound as a clinical candidate for the treatment of cancer.


Assuntos
Antineoplásicos/síntese química , Benzamidas/síntese química , Cinesinas/antagonistas & inibidores , Pirimidinonas/síntese química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Benzamidas/farmacocinética , Benzamidas/farmacologia , Proteínas Sanguíneas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Hepatócitos/metabolismo , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Camundongos , Camundongos Nus , Microssomos Hepáticos/metabolismo , Ligação Proteica , Pirimidinonas/farmacocinética , Pirimidinonas/farmacologia , Ratos , Ratos Wistar , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade
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