Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 73
Filtrar
1.
Bioorg Med Chem Lett ; 75: 128951, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36031020

RESUMO

We report herein, the discovery of BMS-737 (compound 33) as a potent, non-steroidal, reversible small molecule inhibitor demonstrating 11-fold selectivity for CYP17 lyase over CYP17 hydroxylase, as well as a clean xenobiotic CYP profile for the treatment of castration-resistant prostate cancer (CRPC). Extensive SAR studies on the initial lead 1 at three different regions of the molecule resulted in the identification of BMS-737, which demonstrated a robust 83% lowering of testosterone without any significant perturbation of the mineralocorticoid and glucocorticoid levels in cynomologous monkeys in a 1-day PK/PD study.


Assuntos
Liases , Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Antagonistas de Androgênios , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Glucocorticoides , Humanos , Masculino , Mineralocorticoides , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Esteroide 17-alfa-Hidroxilase , Testosterona , Xenobióticos
2.
Exp Cell Res ; 332(2): 267-77, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25486070

RESUMO

Cancer cell survival is frequently dependent on the elevated levels of members of the Bcl-2 family of prosurvival proteins that bind to and inactivate BH3-domain pro-apoptotic cellular proteins. Small molecules that inhibit the protein-protein interactions between prosurvival and proapoptotic Bcl-2 family members (so-called "BH3 mimetics") have a potential therapeutic value, as indicated by clinical findings obtained with ABT-263 (navitoclax), a Bcl-2/Bcl-xL antagonist, and more recently with GDC-0199/ABT-199, a more selective antagonist of Bcl-2. Here, we report study results of the functional role of the prosurvival protein Mcl-1 against a panel of solid cancer cell lines representative of different tumor types. We observed silencing of Mcl-1 expression by small interfering RNAs (siRNAs) significantly reduced viability and induced apoptosis in almost 30% of cell lines tested, including lung and breast adenocarcinoma, as well as glioblastoma derived lines. Most importantly, we provide a mechanistic basis for this sensitivity by showing antagonism of Mcl-1 function with specific BH3 peptides against isolated mitochondria induces Bak oligomerization and cytochrome c release, therefore demonstrating that mitochondria from Mcl-1-sensitive cells depend on Mcl-1 for their integrity and that antagonizing Mcl-1 function is sufficient to induce apoptosis. Thus, our results lend further support for considering Mcl-1 as a therapeutic target in a number of solid cancers and support the rationale for development of small molecule BH3-mimetics antagonists of this protein.


Assuntos
Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Mitocôndrias/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/terapia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética
3.
Exp Cell Res ; 338(2): 251-60, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26302264

RESUMO

Cellular levels of inhibitor of apoptosis (IAP) proteins are elevated in multiple human cancers and their activities often play a part in promoting cancer cell survival by blocking apoptotic pathways, controlling signal transduction pathways and contributing to resistance. These proteins function through interactions of their BIR (baculoviral IAP repeat) protein domains with pathway components and these interactions are endogenously antagonized by Smac/Diablo (second mitochondrial activator of caspases/direct IAP binding protein with low isoelectric point). This report describes development of synthetic smac mimetics (SM) and compares their binding, antiproliferative and anti-tumor activities. All dimeric antagonists inhibit in vitro smac tetrapeptide binding to recombinant IAP proteins, rescue IAP-bound caspase-3 activity and show anti-proliferative activity against human A875 melanoma cells. One heterodimeric SM, SM3, binds tightly to IAP proteins in vitro and slowly dissociates (greater than two hours) from these protein complexes compared to the other antagonists. In addition, in vitro SM anti-proliferation potency is influenced by ABCB1 transporter (ATP-binding cassette, sub-family B; MDR1, P-gp) activities and one antagonist, SM5, does not appear to be an ABCB1 efflux pump substrate. All dimeric smac mimetics inhibit the growth of human melanoma A875 tumors implanted in athymic mice at well-tolerated doses. One antagonist, SM4, shows broad spectrum in vivo anti-tumor activity and modulates known pharmacodynamic markers of IAP antagonism. These data taken together demonstrate the range of diverse dimeric IAP antagonist activities and supports their potential as anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Transporte Biológico/efeitos dos fármacos , Caspase 3/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Mitocondriais/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose , Biomimética/métodos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Células HCT116 , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Ligação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína/efeitos dos fármacos
4.
Bioorg Med Chem Lett ; 25(14): 2809-12, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25987372
5.
J Immunother Cancer ; 11(3)2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36948506

RESUMO

BACKGROUND: The prostate tumor microenvironment (TME) is immunosuppressive, with few effector T cells and enrichment of inhibitory immune populations, leading to limited responses to treatments such as immune checkpoint therapies (ICTs). The immune composition of the prostate TME differs across soft tissue and bone, the most common site of treatment-refractory metastasis. Understanding immunosuppressive mechanisms specific to prostate TMEs will enable rational immunotherapy strategies to generate effective antitumor immune responses. Daratumumab (anti-CD38 antibody) and edicotinib (colony-stimulating factor-1 receptor (CSF-1R) inhibitor) may alter the balance within the prostate TME to promote antitumor immune responses. HYPOTHESIS: Daratumumab or edicotinib will be safe and will alter the immune TME, leading to antitumor responses in localized prostate cancer. PATIENTS AND METHODS: In this presurgical study, patients with localized prostate cancer received 4 weekly doses of daratumumab or 4 weeks of daily edicotinib prior to radical prostatectomy (RP). Treated and untreated control (Gleason score ≥8 in prostate biopsy) prostatectomy specimens and patient-matched pre- and post-treatment peripheral blood mononuclear cells (PBMCs) and bone marrow samples were evaluated. The primary endpoint was incidence of adverse events (AEs). The secondary endpoint was pathologic complete remission (pCR) rate. RESULTS: Twenty-five patients were treated (daratumumab, n=15; edicotinib, n=10). All patients underwent RP without delays. Grade 3 treatment-related AEs with daratumumab occurred in 3 patients (12%), and no ≥grade 3 treatment-related AEs occurred with edicotinib. No changes in serum prostate-specific antigen (PSA) levels or pCRs were observed. Daratumumab led to a decreased frequency of CD38+ T cells, natural killer cells, and myeloid cells in prostate tumors, bone marrow, and PBMCs. There were no consistent changes in CSF-1R+ immune cells in prostate, bone marrow, or PBMCs with edicotinib. Neither treatment induced T cell infiltration into the prostate TME. CONCLUSIONS: Daratumumab and edicotinib treatment was safe and well-tolerated in patients with localized prostate cancer but did not induce pCRs. Decreases in CD38+ immune cells were observed in prostate tumors, bone marrow, and PBMCs with daratumumab, but changes in CSF-1R+ immune cells were not consistently observed with edicotinib. Neither myeloid-targeted agent alone was sufficient to generate antitumor responses in prostate cancer; thus, combinations with agents to induce T cell infiltration (eg, ICTs) will be needed to overcome the immunosuppressive prostate TME.


Assuntos
Antineoplásicos , Neoplasias da Próstata , Masculino , Humanos , Leucócitos Mononucleares/patologia , Antineoplásicos/uso terapêutico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Imunossupressores , Microambiente Tumoral
6.
Cancer Res Commun ; 3(8): 1447-1459, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37546702

RESUMO

Although recent efforts have led to the development of highly effective androgen receptor (AR)-directed therapies for the treatment of advanced prostate cancer, a significant subset of patients will progress with resistant disease including AR-negative tumors that display neuroendocrine features [neuroendocrine prostate cancer (NEPC)]. On the basis of RNA sequencing (RNA-seq) data from a clinical cohort of tissue from benign prostate, locally advanced prostate cancer, metastatic castration-resistant prostate cancer and NEPC, we developed a multi-step bioinformatics pipeline to identify NEPC-specific, overexpressed gene transcripts that encode cell surface proteins. This included the identification of known NEPC surface protein CEACAM5 as well as other potentially targetable proteins (e.g., HMMR and CESLR3). We further showed that cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3) knockdown results in reduced NEPC tumor cell proliferation and migration in vitro. We provide in vivo data including laser capture microdissection followed by RNA-seq data supporting a causal role of CELSR3 in the development and/or maintenance of the phenotype associated with NEPC. Finally, we provide initial data that suggests CELSR3 is a target for T-cell redirection therapeutics. Further work is now needed to fully evaluate the utility of targeting CELSR3 with T-cell redirection or other similar therapeutics as a potential new strategy for patients with NEPC. Significance: The development of effective treatment for patients with NEPC remains an unmet clinical need. We have identified specific surface proteins, including CELSR3, that may serve as novel biomarkers or therapeutic targets for NEPC.


Assuntos
Tumores Neuroendócrinos , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/genética , Tumores Neuroendócrinos/genética , Próstata/metabolismo , Membrana Celular/metabolismo , Caderinas/genética
7.
Bioorg Med Chem ; 20(6): 1961-72, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-22137930

RESUMO

Therapeutic development of a targeted agent involves a series of decisions over additional activities that may be ignored, eliminated or pursued. This paper details the concurrent application of two methods that provide a spectrum of information about the biological activity of a compound: biochemical profiling on a large panel of kinase assays and transcriptional profiling of mRNA responses. Our mRNA profiling studies used a full dose range, identifying subsets of transcriptional responses with differing EC(50)s which may reflect distinct targets. Profiling data allowed prioritization for validation in xenograft models, generated testable hypotheses for active compounds, and informed decisions on the general utility of the series.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , RNA Mensageiro/genética , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Quinase 9 Dependente de Ciclina/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Receptor IGF Tipo 1/genética , Triagem
8.
Prostate Cancer Prostatic Dis ; 25(2): 219-228, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34257408

RESUMO

BACKGROUND: The safety and immunogenicity of JNJ-64041809 (JNJ-809), a live-attenuated, double-deleted Listeria monocytogenes (LADD Lm)-based immunotherapy targeting 4 relevant prostate cancer antigens, was evaluated in a phase 1 study in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: Men with progressive mCRPC who had received ≥2 prior approved therapies were enrolled. Primary study objectives were to determine the recommended phase 2 dose (RP2D) and to evaluate the safety and immunogenicity of JNJ-809. RESULTS: A total of 26 patients received JNJ-809 (1 × 108 CFU (n = 6); 1 × 109 CFU (n = 20)). No dose-limiting toxicities were reported, and 1 × 109 CFU was selected as the RP2D. The most common adverse events (AEs) reported were chills (92%), pyrexia (81%), and fatigue (62%). The most frequent grade ≥3 AEs were lymphopenia (27%) and hypertension (23%). Serious AEs were reported in 27% of patients including 1 patient with grade 3 intestinal obstruction. JNJ-809 transiently induced peripheral cytokines, including interferon-γ, interleukin-10, and tumor necrosis factor-α. Of the 7 patients evaluable for T cell responses at the 1 × 109 CFU dose, evidence of post-treatment antigenic responses were observed in 6 to the Listeria antigen listeriolysin O and in 5 to ≥1 of the 4 encoded tumor antigens. Best overall response was stable disease in 13/25 response-evaluable patients. The study was terminated early as data collected were considered sufficient to evaluate safety and immunogenicity. CONCLUSIONS: JNJ-809 has manageable safety consistent with other LADD Lm-based therapies. Limited antigen-specific immune responses were observed, which did not translate into objective clinical responses.


Assuntos
Listeria monocytogenes , Neoplasias de Próstata Resistentes à Castração , Humanos , Imunoterapia/efeitos adversos , Listeria monocytogenes/genética , Masculino , Neoplasias de Próstata Resistentes à Castração/patologia
9.
Prostate ; 71(5): 480-8, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20878947

RESUMO

BACKGROUND: Androgen receptor (AR) antagonists are part of the standard of care for prostate cancer. Despite the almost inevitable development of resistance in prostate tumors to AR antagonists, no new AR antagonists have been approved for over a decade. Treatment failure is due in part to mutations that increase activity of AR in response to lower ligand concentrations as well as to mutations that result in AR response to a broader range of ligands. The failure to discover new AR antagonists has occurred in the face of continued research; to enable progress, a clear understanding of the reasons for failure is required. METHODS: Non-clinical drug safety studies and safety pharmacology assays were performed on previously approved AR antagonists (bicalutamide, flutamide, nilutamide), next generation antagonists in clinical testing (MDV3100, BMS-641988), and a pre-clinical drug candidate (BMS-501949). In addition, non-clinical studies with AR mutant mice, and EEG recordings in rats were performed. Non-clinical findings are compared to disclosures of clinical trial results. RESULTS: As a drug class, AR antagonists cause seizure in animals by an off-target mechanism and are found in vitro to inhibit GABA-A currents. Clinical trials of candidate next generation AR antagonists identify seizure as a clinical safety risk. CONCLUSIONS: Non-clinical drug safety profiles of the AR antagonist drug class create a significant barrier to the identification of next generation AR antagonists. GABA-A inhibition is a common off-target activity of approved and next generation AR antagonists potentially explaining some side effects and safety hazards of this class of drugs.


Assuntos
Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/toxicidade , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Antagonistas de Androgênios/farmacocinética , Animais , Cães , Descoberta de Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neoplasias da Próstata/metabolismo , Ratos , Ratos Sprague-Dawley
11.
J Med Chem ; 64(2): 909-924, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33470111

RESUMO

Persistent androgen receptor (AR) activation drives therapeutic resistance to second-generation AR pathway inhibitors and contributes to the progression of advanced prostate cancer. One resistance mechanism is point mutations in the ligand binding domain of AR that can transform antagonists into agonists. The AR F877L mutation, identified in patients treated with enzalutamide or apalutamide, confers resistance to both enzalutamide and apalutamide. Compound 4 (JNJ-pan-AR) was identified as a pan-AR antagonist with potent activity against wild-type and clinically relevant AR mutations including F877L. Metabolite identification studies revealed a latent bioactivation pathway associated with 4. Subsequent lead optimization of 4 led to amelioration of this pathway and nomination of 5 (JNJ-63576253) as a clinical stage, next-generation AR antagonist for the treatment of castration-resistant prostate cancer (CRPC).


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Nitrilas/farmacologia , Picolinas/farmacologia , Piperidinas/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Piridinas/farmacologia , Compostos de Espiro/farmacologia , Antagonistas de Receptores de Andrógenos/farmacocinética , Antagonistas de Receptores de Andrógenos/uso terapêutico , Animais , Biotransformação , Linhagem Celular Tumoral , Cães , Descoberta de Drogas , Resistencia a Medicamentos Antineoplásicos/genética , Hepatócitos/metabolismo , Humanos , Masculino , Modelos Moleculares , Mutação , Nitrilas/farmacocinética , Nitrilas/uso terapêutico , Picolinas/farmacocinética , Picolinas/uso terapêutico , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Neoplasias da Próstata/genética , Neoplasias de Próstata Resistentes à Castração/genética , Piridinas/farmacocinética , Piridinas/uso terapêutico , Ratos , Compostos de Espiro/farmacocinética , Compostos de Espiro/uso terapêutico , Relação Estrutura-Atividade
12.
Mol Cancer Ther ; 20(5): 763-774, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33649102

RESUMO

Numerous mechanisms of resistance arise in response to treatment with second-generation androgen receptor (AR) pathway inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Among these, point mutations in the ligand binding domain can transform antagonists into agonists, driving the disease through activation of AR signaling. To address this unmet need, we report the discovery of JNJ-63576253, a next-generation AR pathway inhibitor that potently abrogates AR signaling in models of human prostate adenocarcinoma. JNJ-63576253 is advancing as a clinical candidate with potential effectiveness in the subset of patients who do not respond to or are progressing while on second-generation AR-targeted therapeutics.


Assuntos
Antagonistas de Receptores de Andrógenos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Domínios Proteicos/genética , Antagonistas de Receptores de Andrógenos/farmacologia , Animais , Linhagem Celular Tumoral , Humanos , Ligantes , Masculino , Camundongos , Modelos Moleculares , Mutação , Ratos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Cell Chem Biol ; 28(2): 134-147.e14, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33086052

RESUMO

Castration-resistant prostate cancers (CRPCs) lose sensitivity to androgen-deprivation therapies but frequently remain dependent on oncogenic transcription driven by the androgen receptor (AR) and its splice variants. To discover modulators of AR-variant activity, we used a lysate-based small-molecule microarray assay and identified KI-ARv-03 as an AR-variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted in KB-0742, an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo, oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptores Androgênicos/genética , Transcrição Gênica/efeitos dos fármacos , Antagonistas de Receptores de Andrógenos/uso terapêutico , Animais , Linhagem Celular Tumoral , Quinase 9 Dependente de Ciclina/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Neoplasias de Próstata Resistentes à Castração/genética , Inibidores de Proteínas Quinases/uso terapêutico
14.
Mol Cell Biol ; 27(8): 3165-75, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17296734

RESUMO

Type I insulin-like growth factor receptor (IGF-IR) can transform mouse fibroblasts; however, little is known about the transforming potential of IGF-IR in human fibroblasts or epithelial cells. We found that overexpression of a constitutively activated IGF-IR (CD8-IGF-IR) was sufficient to cause transformation of immortalized human mammary epithelial cells and growth in immunocompromised mice. Furthermore, CD8-IGF-IR caused cells to undergo an epithelial-to-mesenchymal transition (EMT) which was associated with dramatically increased migration and invasion. The EMT was mediated by the induction of the transcriptional repressor Snail and downregulation of E-cadherin. NF-kappaB was highly active in CD8-IGF-IR-MCF10A cells, and both increased levels of Snail and the EMT were partially reversed by blocking NF-kappaB or IGF-IR activity. This study places IGF-IR among a small group of oncogenes that, when overexpressed alone, can confer in vivo tumorigenic growth of MCF10A cells and indicates the hierarchy in the mechanism of IGF-IR-induced EMT.


Assuntos
Transformação Celular Neoplásica , Células Epiteliais/citologia , Glândulas Mamárias Humanas/citologia , Mesoderma/citologia , NF-kappa B/metabolismo , Receptor IGF Tipo 1/metabolismo , Fatores de Transcrição/metabolismo , Animais , Benzimidazóis/farmacologia , Antígenos CD8/metabolismo , Caderinas/genética , Transformação Celular Neoplásica/efeitos dos fármacos , Colágeno/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Combinação de Medicamentos , Células Epiteliais/efeitos dos fármacos , Genes Reguladores , Humanos , Laminina/efeitos dos fármacos , Glândulas Mamárias Humanas/efeitos dos fármacos , Glândulas Mamárias Humanas/crescimento & desenvolvimento , Camundongos , Modelos Biológicos , Morfogênese/efeitos dos fármacos , Proteoglicanas/efeitos dos fármacos , Piridonas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Proteínas Recombinantes de Fusão/metabolismo , Fatores de Transcrição da Família Snail , Transplante Heterólogo
15.
Bioorg Med Chem Lett ; 20(10): 3182-5, 2010 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-20399649

RESUMO

A series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one were synthesized to modulate CYP3A4 inhibition and improve aqueous solubility of our prototypical compound BMS-536924 (1), while maintaining potent IGF-1R inhibitory activity. Structure-activity and structure-solubility studies led to the identification of BMS-577098 (27), which demonstrates oral in vivo efficacy in animal models. The improvement was achieved by replacing morpholine with more polar bio-isoster piperazine and modulating the basicity of distal nitrogen with appropriate substitutions.


Assuntos
Benzimidazóis/química , Piperazinas/química , Inibidores de Proteínas Quinases/química , Piridonas/química , Administração Oral , Animais , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Humanos , Camundongos , Camundongos Nus , Piperazinas/síntese química , Piperazinas/farmacocinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Piridonas/síntese química , Piridonas/farmacocinética , Piridonas/farmacologia , Ratos , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Bioorg Med Chem Lett ; 20(5): 1744-8, 2010 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-20153189
18.
Clin Cancer Res ; 15(10): 3251-5, 2009 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-19447877

RESUMO

The understanding of the key role that androgens play on the normal and pathological physiology of the prostate guided the development of different therapies for the treatment of locally advanced or metastatic prostate cancer (PCa). These so-called androgen deprivation therapies include surgical or chemical castration, achieved by the administration of gonadotropin-releasing hormone analogs; inhibition of steroidogenic enzymes; and finally, blocking of the binding of androgens to their receptor (AR) by the use of antiandrogens. Despite an excellent initial response, in approximately 2 to 3 years, most of these patients will succumb to the castration resistant form of the disease. Remarkably, even in the presence of castration levels of circulating androgens, these tumors are still dependent on a functional AR, and several molecular mechanisms have been proposed to explain this phenomenon. These include: (1) gene amplification and increased expression of the AR mRNA and protein, (2) selection of mutations in the AR that confer broader ligand specificity, (3) changes in the ratios or expression between the AR and its coregulators, (4) increased expression of steroidogenic enzymes, and (5) up-regulation of cross-talk signal transduction pathways that can activate the AR in a ligand-independent manner. We will summarize how these molecular hypotheses are being tested in the clinic by the latest therapeutic modalities.


Assuntos
Androgênios/metabolismo , Orquiectomia , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Antagonistas de Androgênios/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Modelos Biológicos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Transdução de Sinais/efeitos dos fármacos
19.
Clin Cancer Res ; 15(1): 226-37, 2009 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19118050

RESUMO

PURPOSE: This study aimed to test the ability of a new insulin-like growth factor receptor (IGF-IR) tyrosine kinase inhibitor, BMS-536924, to reverse the ability of constitutively active IGF-IR (CD8-IGF-IR) to transform MCF10A cells, and to examine the effect of the inhibitor on a range of human breast cancer cell lines. EXPERIMENTAL DESIGN: CD8-IGF-IR-MCF10A cells were grown in monolayer culture, three-dimensional (3D) culture, and as xenografts, and treated with BMS-536924. Proliferation, cell cycle, polarity, and apoptosis were measured. Twenty-three human breast cancer cell lines were treated in monolayer culture with BMS-536924, and cell viability was measured. MCF7, MDA-MB-231, and MDA-MB-435 were treated with BMS-536924 in monolayer and 3D culture, and proliferation, migration, polarity, and apoptosis were measured. RESULTS: Treatment of CD8-IGF-IR-MCF10A cells grown in 3D culture with BMS-536924 caused a blockade of proliferation, restoration of apical-basal polarity, and enhanced apoptosis, resulting in a partial phenotypic reversion to normal acini. In monolayer culture, BMS-536924 induced a dose-dependent inhibition of proliferation, with an accumulation of cells in G(0)/G(1,), and completely blocked CD8-IGF-IR-induced migration, invasion, and anchorage-independent growth. CD8-IGF-IR-MCF10A xenografts treated with BMS-536924 (100 mg/kg/day) showed a 76% reduction in xenograft volume. In a series of 23 human breast cancer cell lines, BMS-536924 inhibited monolayer proliferation of 16 cell lines. Most strikingly, treatment of MCF7 cells grown in 3D culture with BMS-536924 caused blockade of proliferation, and resulted in the formation of hollow polarized lumen. CONCLUSIONS: These results show that the new small molecule BMS-536924 is an effective inhibitor of IGF-IR, causing a reversion of an IGF-IR - mediated transformed phenotype.


Assuntos
Benzimidazóis/farmacologia , Neoplasias da Mama/patologia , Transformação Celular Neoplásica/efeitos dos fármacos , Glândulas Mamárias Humanas/efeitos dos fármacos , Piridonas/farmacologia , Receptores de Somatomedina/antagonistas & inibidores , Apoptose , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células Epiteliais/efeitos dos fármacos , Feminino , Humanos , Receptores de Somatomedina/metabolismo
20.
Anal Biochem ; 392(1): 59-69, 2009 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-19497292

RESUMO

Eg5 is a kinesin whose inhibition leads to cycle arrest during mitosis, making it a potential therapeutic target in cancers. Circular dichroism and isothermal titration calorimetry of our pyrrolotriazine-4-one series of inhibitors with Eg5 motor domain revealed enhanced binding in the presence of adenosine 5'-diphosphate (ADP). Using this information, we studied the interaction of this series with ADP-Eg5 complexes using a thermal shift assay. We measured up to a 7 degrees C increase in the thermal melting (T(m)) of Eg5 for an inhibitor that produced IC(50) values of 60 and 130 nM in microtubule-dependent adenosine triphosphatase (ATPase) and cell-based cytotoxicity assays, respectively. In general, the inhibitor potency of the pyrrolotriazine-4-one series in in vitro biological assays correlated with the magnitude of the thermal stability enhancement of ADP-Eg5. The thermal shift assay also confirmed direct binding of Eg5 inhibitors identified in a high-throughput screen and demonstrated that the thermal shift assay is applicable to a range of chemotypes and can be useful in evaluating both potent (nM) and relatively weakly binding (microM) leads. Overall, the thermal shift assay was found to be an excellent biophysical method for evaluating direct binding of a large number of compounds to Eg5, and it complemented the catalytic assay screens by providing an alternative determination of inhibitor potency.


Assuntos
Bioquímica/métodos , Cinesinas/química , Pirróis/análise , Pirróis/química , Triazinas/análise , Triazinas/química , Difosfato de Adenosina/metabolismo , Fenômenos Biofísicos , Calorimetria , Linhagem Celular Tumoral , Dicroísmo Circular , Humanos , Cinesinas/metabolismo , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Ligação Proteica , Desnaturação Proteica , Dobramento de Proteína , Estrutura Terciária de Proteína , Temperatura
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA