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1.
Cell Physiol Biochem ; 52(6): 1553-1568, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31135123

RESUMO

BACKGROUND/AIMS: Despite, several studies demonstrating pro-metastatic effects of the metalloproteinase ADAMTS1 in breast cancer, its role in facilitating the metastatic cascade remains unclear. To date there have been limited studies that have examined the expression of ADAMTS1 in primary and metastatic breast cancer tissues. METHODS: We assessed ADAMTS1 mRNA levels in publically available breast cancer sets and analysed ADAMTS1 protein levels by immunohistochemistry in breast tissue microarrays containing normal breast tissue (n=9), primary invasive ductal breast carcinomas (n=79) and metastatic lesions (n=58). To understand the underlying events influenced by ADAMTS1 and provide a mechanism by which tumors expressing this protease promote metastasis, we assessed the ability of PyMT/Adamts1+/+, PyMT/Adamts1+/- and PyMT/Adamts1-/- primary mammary cancer cells to adhere to matrigel and migrate or invade towards a chemoattractive environment. RESULTS: High ADAMTS1 expression was associated with reduced disease-free survival, distant metastasis free-survival and overall survival in breast cancer patients with node negative disease. Although ADAMTS1 expression was reduced in primary breast cancers compared to normal tissue and not elevated in metastatic lesions, high ADAMTS1 immunostaining was associated with a higher number of positive lymph nodes (p=0.006) and the presence of distant metastasis (p=0.023). Depletion of Adamts1 in mammary cancer cells impeded their adhesion to a biological matrix substratum and diminished cell migration but not invasion. CONCLUSION: The effects observed on cell adhesion and migration demonstrates a potential mechanism whereby ADAMTS1 promotes breast cancer metastasis.


Assuntos
Proteína ADAMTS1/metabolismo , Neoplasias da Mama/patologia , Proteínas da Matriz Extracelular/metabolismo , Proteína ADAMTS1/genética , Animais , Neoplasias da Mama/mortalidade , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Camundongos , Camundongos Transgênicos , Estadiamento de Neoplasias , Prognóstico
3.
Chem Biol ; 21(11): 1476-85, 2014 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-25459660

RESUMO

There has been a resurgence of interest in the development of androgen receptor (AR) inhibitors with alternative modes of action to overcome the development of resistance to current therapies. We demonstrated previously that one promising strategy for combatting mutation-driven drug resistance is to target the Binding Function 3 (BF3) pocket of the receptor. Here we report the development of a potent BF3 inhibitor, 3-(2,3-dihydro-1H-indol-2-yl)-1H-indole, which demonstrates excellent antiandrogen potency and anti-PSA activity and abrogates the androgen-induced proliferation of androgen-sensitive (LNCaP) and enzalutamide-resistant (MR49F) PCa cell lines. Moreover, this compound effectively reduces the expression of AR-dependent genes in PCa cells and effectively inhibits tumor growth in vivo in both LNCaP and MR49F xenograft models. These findings provide evidence that targeting the AR BF3 pocket represents a viable therapeutic approach to treat patients with advanced and/or resistant prostate cancer.


Assuntos
Antagonistas de Androgênios/química , Antagonistas de Androgênios/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Indóis/química , Indóis/farmacologia , Receptores Androgênicos/química , Antagonistas de Androgênios/uso terapêutico , Animais , Benzamidas , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Indóis/uso terapêutico , Masculino , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Nitrilas , Feniltioidantoína/análogos & derivados , Feniltioidantoína/toxicidade , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Estrutura Terciária de Proteína , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Transplante Heterólogo
4.
J Med Chem ; 57(15): 6458-67, 2014 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-25062331

RESUMO

The human androgen receptor (AR) is considered as a master regulator in the development and progression of prostate cancer (PCa). As resistance to clinically used anti-AR drugs remains a major challenge for the treatment of advanced PCa, there is a pressing need for new anti-AR therapeutic avenues. In this study, we identified a binding site on the DNA binding domain (DBD) of the receptor and utilized virtual screening to discover a set of micromolar hits for the target. Through further exploration of the most potent hit (1), a structural analogue (6) was identified demonstrating 10-fold improved anti-AR potency. Further optimization resulted in a more potent synthetic analogue (25) with anti-AR potency comparable to a newly FDA-approved drug Enzalutamide. Site-directed mutagenesis demonstrated that the developed inhibitors do interact with the intended target site. Importantly, the AR DBD inhibitors could effectively inhibit the growth of Enzalutamide-resistant cells as well as block the transcriptional activity of constitutively active AR splice variants, such as V7.


Assuntos
Antagonistas de Receptores de Andrógenos/química , Antineoplásicos/química , DNA/metabolismo , Imidazóis/química , Morfolinas/química , Receptores Androgênicos/metabolismo , Tiazóis/química , Antagonistas de Receptores de Andrógenos/síntese química , Antagonistas de Receptores de Andrógenos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzamidas , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Simulação por Computador , Bases de Dados de Compostos Químicos , Resistencia a Medicamentos Antineoplásicos , Humanos , Imidazóis/síntese química , Imidazóis/farmacologia , Masculino , Conformação Molecular , Simulação de Acoplamento Molecular , Morfolinas/síntese química , Morfolinas/farmacologia , Mutação , Nitrilas , Feniltioidantoína/análogos & derivados , Feniltioidantoína/farmacologia , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Compostos de Pirvínio/química , Compostos de Pirvínio/farmacologia , Ratos , Receptores Androgênicos/genética , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologia , Tiofenos/síntese química , Tiofenos/química , Tiofenos/farmacologia , Transcrição Gênica
5.
J Med Chem ; 57(15): 6867-72, 2014 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-25025737

RESUMO

To overcome resistance to conventional anti-androgens of human androgen receptor (AR), the allosteric site of the AR binding function 3 (BF3) was investigated as an alternative target for small molecule therapeutics. A library of 1H-indole-2-carboxamides were discovered as BF3 inhibitors and exhibited strong antiproliferative activity against LNCaP and enzalutamide-resistant prostate cancer cell lines. Several of the lead compounds may prove of particular benefit as a novel alternative treatment for castration-resistant prostate cancers.


Assuntos
Amidas/química , Antineoplásicos/química , Indóis/química , Receptores Androgênicos/metabolismo , Sítio Alostérico , Amidas/síntese química , Amidas/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/síntese química , Indóis/farmacologia , Masculino , Modelos Moleculares , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
6.
Mol Cancer Ther ; 12(11): 2425-35, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23939374

RESUMO

The human androgen receptor plays a major role in the development and progression of prostate cancer and represents a well-established drug target. All clinically approved androgen receptor antagonists possess similar chemical structures and exhibit the same mode of action on the androgen receptor. Although initially effective, resistance to these androgen receptor antagonists usually develops and the cancer quickly progresses to castration-resistant and metastatic states. Yet even in these late-stage patients, the androgen receptor is critical for the progression of the disease. Thus, there is a continuing need for novel chemical classes of androgen receptor antagonists that could help overcome the problem of resistance. In this study, we implemented and used the synergetic combination of virtual and experimental screening to discover a number of new 10-benzylidene-10H-anthracen-9-ones that not only effectively inhibit androgen receptor transcriptional activity, but also induce almost complete degradation of the androgen receptor. Of these 10-benzylidene-10H-anthracen-9-one analogues, a lead compound (VPC-3033) was identified that showed strong androgen displacement potency, effectively inhibited androgen receptor transcriptional activity, and possesses a profound ability to cause degradation of androgen receptor. Notably, VPC-3033 exhibited significant activity against prostate cancer cells that have already developed resistance to the second-generation antiandrogen enzalutamide (formerly known as MDV3100). VPC-3033 also showed strong antiandrogen receptor activity in the LNCaP in vivo xenograft model. These results provide a foundation for the development of a new class of androgen receptor antagonists that can help address the problem of antiandrogen resistance in prostate cancer.


Assuntos
Antagonistas de Receptores de Andrógenos/química , Antagonistas de Receptores de Andrógenos/farmacologia , Antracenos/química , Antracenos/farmacologia , Compostos de Benzilideno/química , Compostos de Benzilideno/farmacologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/metabolismo , Antagonistas de Receptores de Andrógenos/metabolismo , Antagonistas de Receptores de Andrógenos/uso terapêutico , Animais , Antracenos/metabolismo , Antracenos/uso terapêutico , Benzamidas , Compostos de Benzilideno/metabolismo , Compostos de Benzilideno/uso terapêutico , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular Tumoral , Bases de Dados Factuais , Modelos Animais de Doenças , Células HeLa , Humanos , Masculino , Camundongos Nus , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Nitrilas , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/genética , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Med Chem ; 56(3): 1136-48, 2013 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-23301637

RESUMO

The human androgen receptor (AR) is a proven therapeutic target in prostate cancer. All current antiandrogens, such as Bicalutamide, Flutamide, Nilutamide, and Enzalutamide, target the buried hydrophobic androgen binding pocket of this protein. However, effective resistance mechanisms against these therapeutics exist such as mutations occurring at the target site. To overcome these limitations, the surface pocket of the AR called binding function 3 (BF3) was characterized as an alternative target for small molecule therapeutics. A number of AR inhibitors directly targeting the BF3 were previously identified by us ( J. Med. Chem. 2011 . 54 , 8563 ). In the current study, based on the prior results, we have developed structure-activity relationships that allowed designing a series of 2-((2-phenoxyethyl)thio)-1H-benzimidazole and 2-((2-phenoxyethyl)thio)-1H-indole as lead BF3 inhibitors. Some of the developed BF3 ligands demonstrated significant antiandrogen potency against LNCaP and Enzalutamide-resistant prostate cancer cell lines.


Assuntos
Benzimidazóis/metabolismo , Receptores Androgênicos/metabolismo , Benzimidazóis/química , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Masculino , Estrutura Molecular , Antígeno Prostático Específico/metabolismo
8.
J Chem Inf Model ; 53(1): 123-30, 2013 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-23278403

RESUMO

Androgen receptor (AR) plays a critical role in the development and progression of prostate cancer (PCa). The AR hormone-binding site (HBS) is intensively studied and represents the target area for current antiandrogens including Bicalutamide and structurally related Enzalutamide. As resistance to antiandrogens invariably emerges in advanced prostate cancer, there exists a high medical need for the identification and development of novel AR antagonists of different chemotypes. Given the wealth of structural information on the AR in complex with a variety of ligands, we have applied an integrated structure- and ligand-based virtual screening methodology to identify novel AR antagonists. Virtual hits generated by a consensus voting approach were experimentally evaluated and resulted in the discovery of a number of structurally diverse submicromolar antagonists of the AR. In particular, one identified compound demonstrated anti-AR potency in vitro that is comparable to the clinically used Bicalutamide. These results set a ground for the development of novel classes of PCa drugs that are structurally different from current AR antagonists.


Assuntos
Antagonistas de Receptores de Andrógenos/química , Antagonistas de Receptores de Andrógenos/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Receptores Androgênicos/metabolismo , Antagonistas de Receptores de Andrógenos/metabolismo , Androgênios/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Antígeno Prostático Específico/metabolismo , Relação Quantitativa Estrutura-Atividade , Receptores Androgênicos/química , Interface Usuário-Computador
9.
Am J Pathol ; 179(6): 3075-85, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22001177

RESUMO

A disintegrin and metalloprotease with thrombospondin motifs protein 1 (ADAMTS1) is a protease commonly up-regulated in metastatic carcinoma. Its overexpression in cancer cells promotes experimental metastasis, but whether ADAMTS1 is essential for metastatic progression is unknown. To address this question, we investigated mammary cancer progression and spontaneous metastasis in the MMTV-PyMT mouse mammary tumor model in Adamts1 knockout mice. Adamts1(-/-)/PyMT mice displayed significantly reduced mammary tumor and lung metastatic tumor burden and increased survival, compared with their wild-type and heterozygous littermates. Histological examination revealed an increased proportion of tumors with ductal carcinoma in situ and a lower proportion of high-grade invasive tumors in Adamts1(-/-)/PyMT mice, compared with Adamts1(+/+)/PyMT mice. Increased apoptosis with unaltered proliferation and vascular density in the Adamts1(-/-)/PyMT tumors suggested that reduced cell survival accounts for the lower tumor burden in ADAMTS1-deficient mice. Furthermore, Adamts1(-/-) tumor stroma had significantly lesser amounts of proteolytically cleaved versican and increased numbers of CD45(+) leukocytes. Characterization of immune cell gene expression indicated that cytotoxic cell activation was increased in Adamts1(-/-) tumors, compared with Adamts1(+/+) tumors. This finding is supported by significantly elevated IL-12(+) cell numbers in Adamts1(-/-) tumors. Thus, in vivo ADAMTS1 may promote mammary tumor growth and progression to metastasis in the PyMT model and is a potential therapeutic target to prevent metastatic breast cancer.


Assuntos
Proteínas ADAM/genética , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/genética , Proteínas ADAM/metabolismo , Proteína ADAMTS1 , Animais , Apoptose/genética , Proliferação de Células , Progressão da Doença , Feminino , Estimativa de Kaplan-Meier , Antígenos Comuns de Leucócito , Neoplasias Pulmonares/genética , Metástase Linfática , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neovascularização Patológica/genética , Linfócitos T/imunologia , Células Th1/imunologia , Carga Tumoral/genética , Versicanas/metabolismo
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