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1.
Int J Mol Sci ; 22(4)2021 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-33672769

RESUMEN

Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol (DES; an estrogen) produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the first-line PCa therapy. Insufficiency of ADT over time leads to castration-resistant PCa (CRPC) in which the AR axis is still active, despite castrate levels of circulating androgens. Despite the approval and use of multiple generations of competitive AR antagonists (antiandrogens), antiandrogen resistance emerges rapidly in CRPC due to several mechanisms, mostly converging in the AR axis. Recent evidence from multiple groups have defined noncompetitive or noncanonical direct binding sites on AR that can be targeted to inhibit the AR axis. This review discusses new developments in the PCa treatment paradigm that includes the next-generation molecules to noncanonical sites, proteolysis targeting chimera (PROTAC), or noncanonical N-terminal domain (NTD)-binding of selective AR degraders (SARDs). A few lead compounds targeting each of these novel noncanonical sites or with SARD activity are discussed. Many of these ligands are still in preclinical development, and a few early clinical leads have emerged, but successful late-stage clinical data are still lacking. The breadth and diversity of targets provide hope that optimized noncanonical inhibitors and/or SARDs will be able to overcome antiandrogen-resistant CRPC.


Asunto(s)
Antagonistas de Receptores Androgénicos/uso terapéutico , Terapia Molecular Dirigida , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/química , Antagonistas de Receptores Androgénicos/farmacología , Animales , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Proteolisis/efectos de los fármacos
2.
Eur J Med Chem ; 216: 113307, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33652354

RESUMEN

Androgen receptor (AR) is an effective therapeutic target for the treatment of prostate cancer. We report herein the design, synthesis, and biological evaluation of highly effective proteolysis targeting chimeras (PROTAC) androgen receptor (AR) degraders, such as compound A031. It could induce the degradation of AR protein in VCaP cell lines in a time-dependent manner, achieving the IC 50 value of less than 0.25 µM. The A031 is 5 times less toxic than EZLA and works with an appropriate half-life (t 1/2) or clearance rate (Cl). Also, it has a significant inhibitory effect on tumor growth in zebrafish transplanted with human prostate cancer (VCaP). Therefore, A031 provides a further idea of developing novel drugs for prostate cancer.


Asunto(s)
Antagonistas de Receptores Androgénicos/química , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/farmacocinética , Antagonistas de Receptores Androgénicos/farmacología , Antagonistas de Receptores Androgénicos/uso terapéutico , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Proteolisis , Ratas , Ratas Sprague-Dawley , Receptores Androgénicos/genética , Relación Estructura-Actividad , Tasa de Supervivencia , Trasplante Heterólogo , Pez Cebra/crecimiento & desarrollo , Pez Cebra/fisiología
3.
Chemosphere ; 262: 128313, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33182081

RESUMEN

Androgens and androgen receptor regulate a variety of biological effects in the human body. The impaired functioning of androgen receptor may have different adverse health effects from cancer to infertility. Therefore, it is important to determine whether new chemicals have any binding activity and act as androgen agonists or antagonists before commercial use. Due to the large number of chemicals that require experimental testing, the computational methods are a viable alternative. Therefore, the aim of the present study was to develop predictive QSAR models for classifying compounds according to their activity at the androgen receptor. A large data set of chemicals from the CoMPARA project was used for this purpose and random forest classification models have been developed for androgen binding, agonistic, and antagonistic activity. In addition, a unique effort has been made for multi-class approach that discriminates between inactive compounds, agonists and antagonists simultaneously. For the evaluation set, the classification models predicted agonists with 80% of accuracy and for the antagonists' and binders' the respective metrics were 72% and 78%. Combining agonists, antagonists and inactive compounds into a multi-class approach added complexity to the modelling task and resulted to 64% prediction accuracy for the evaluation set. Considering the size of the training data sets and their imbalance, the achieved evaluation accuracy is very good. The final classification models are available for exploring and predicting at QsarDB repository (https://doi.org/10.15152/QDB.236).


Asunto(s)
Antagonistas de Receptores Androgénicos/clasificación , Andrógenos/clasificación , Modelos Químicos , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/química , Antagonistas de Receptores Androgénicos/farmacología , Andrógenos/química , Andrógenos/farmacología , Humanos , Aprendizaje Automático , Unión Proteica , Relación Estructura-Actividad Cuantitativa
4.
Eur J Med Chem ; 192: 112156, 2020 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-32114360

RESUMEN

Androgen receptor (AR) plays important roles in the development of prostate cancer (PCa), and therefore it has been regarded as the most important therapeutic target for both hormone-sensitive prostate cancer (HSPC) and advanced PCa. In this study, a novel hit (C18) with IC50 of 2.4 µM against AR transcriptional activity in LNCaP cell was identified through structure-based virtual screening based on molecular docking and free energy calculations. The structure-activity relationship analysis and structural optimization of C18 resulted in the discovery of a structural analogue (AT2), a more potent AR antagonist with 16-fold improved anti-AR potency. Further assays indicated that AT2 was capable of effectively inhibiting the transcriptional function of AR and blocking the nuclear translocation of AR like the second-generation AR antagonists. The antagonists discovered in this study may be served as the promising lead compounds for the development of AR-driven PCa therapeutics.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Quinolonas/farmacología , Células 3T3 , Antagonistas de Receptores Androgénicos/síntesis química , Antagonistas de Receptores Androgénicos/química , Animales , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Simulación del Acoplamiento Molecular , Estructura Molecular , Quinolonas/síntesis química , Quinolonas/química , Relación Estructura-Actividad , Células Tumorales Cultivadas
5.
Eur J Med Chem ; 192: 112196, 2020 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-32169785

RESUMEN

Prostate cancer (PC) is the most diagnosed type of malignancy in men and the major frequently cause of cancer-related death worldwide. The androgen receptor (AR) has become a promising drug target for the treatment of PC. Here, we reported the design, optimization and evaluation of pyridine tetrahydroisoquinoline thiohydantoin derivatives with improved activity and safety as potent AR antagonists. The most promising compound 42f exhibited potent inhibitory activity on AR and strongly blocked AR nuclear translocation. Moreover, 42f displayed promising in vitro antitumor activity toward AR-dependent prostate cancer cell lines (LNCaP) and also demonstrated therapeutic effects in LNCaP xenograft tumor model in mice (TGI: 79%) with no apparent toxicity observed in vivo. More importantly, 42f showed negligible penetration of the brain-blood barrier (BBB) compared with enzalutamide. These results provide a foundation for the development of a new class of androgen receptor antagonists for potential therapeutics against PC with lower seizurogenic risk for patients.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Antineoplásicos/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Piridinas/farmacología , Receptores Androgénicos/metabolismo , Tetrahidroisoquinolinas/farmacología , Tiohidantoínas/farmacología , Antagonistas de Receptores Androgénicos/síntesis química , Antagonistas de Receptores Androgénicos/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Piridinas/síntesis química , Piridinas/química , Relación Estructura-Actividad , Tetrahidroisoquinolinas/síntesis química , Tetrahidroisoquinolinas/química , Tiohidantoínas/síntesis química , Tiohidantoínas/química , Células Tumorales Cultivadas
6.
Food Chem ; 311: 125918, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-31869647

RESUMEN

Multilayer materials used in food packaging are commonly manufactured with a polyurethane adhesive layer in its structure that may contain cyclic esters oligomers as potential migrants. However, little is known about their toxicity. In this work, two cyclic esters of polyurethane are evaluated in migration from 20 multilayer packaging samples. They were composed by adipic acid (AA), diethylene glycol (DEG) and isophthalic acid (IPA) and their structure was AA-DEG and AA-DEG-IPA-DEG. The concentration of these compounds in migration exceeded the maximum level established by Regulation EU/10/2011 (10 ng g-1). Bioaccessibility of both compounds was evaluated by studying gastric and intestinal digestion. The studies showed that the concentration of the compounds decreased during digestion and that their hydrolysed molecules increased. Furthermore, endocrine activity in vitro assays were performed. A weak androgen receptor antagonism was identified, whereas no arylhydrocarbon receptor activity or binding to the thyroid hormone transport protein was found.


Asunto(s)
Adhesivos/química , Embalaje de Alimentos/instrumentación , Poliésteres/química , Poliuretanos/química , Adipatos/química , Adipatos/toxicidad , Antagonistas de Receptores Androgénicos/química , Antagonistas de Receptores Androgénicos/toxicidad , Línea Celular , Glicoles de Etileno/química , Glicoles de Etileno/toxicidad , Contaminación de Alimentos/análisis , Humanos , Ácidos Ftálicos/química , Ácidos Ftálicos/toxicidad , Poliuretanos/toxicidad
7.
Biomater Sci ; 8(2): 673-681, 2020 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-31769454

RESUMEN

Cell membrane-cloaked nanotechnology has attracted increasing attention owing to its unique bionic properties, such as specific recognition and biocompatibility conferred by the integrated membrane structure and receptors. However, this technology is limited by the dissociation of the cell membrane from its carrier. Here, we report a novel type of cell membrane-cloaked modified magnetic nanoparticle with good stability in drug discovery. High α1A-adrenergic receptor (α1A-AR) expressing HEK293 cell membrane-cloaked magnetic nanogrippers (α1A/MNGs) were used as a platform for the specific targeting and binding of α1A-AR antagonists as candidate bioactive compounds from traditional Chinese medicine (TCM). Furthermore, using a dynamic covalent bonding approach, α1A/MNGs showed great stability with positive control drug recoveries of α1A/MNGs showing almost no decline after use in five adsorption-desorption cycles. Moreover, the α1A/MNGs possessed a unilamellar membrane with magnetic features and exhibited good binding capacity and selectivity. Ultimately, TCM and pharmacological studies of the bioactivity of the screened compounds confirmed the considerable targeting and binding capability of α1A/MNGs. Application of aldehyde group modification in this drug-targeting concept further improved biomaterial stability and paves the way for the development of new drug discovery strategies. More importantly, the successful application of α1A/MNGs provides new insights into methodologies to improve the integration of cell membranes with the nanoparticle platform.


Asunto(s)
Antagonistas de Receptores Androgénicos/química , Membrana Celular/química , Descubrimiento de Drogas , Medicamentos Herbarios Chinos/química , Nanopartículas del Metal/química , Receptores Adrenérgicos alfa 1/química , Antagonistas de Receptores Androgénicos/farmacología , Animales , Membrana Celular/metabolismo , Estabilidad de Medicamentos , Medicamentos Herbarios Chinos/farmacología , Células HEK293 , Humanos , Masculino , Medicina China Tradicional , Conejos , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos alfa 1/metabolismo
8.
J Med Chem ; 62(24): 11218-11231, 2019 12 26.
Artículo en Inglés | MEDLINE | ID: mdl-31804827

RESUMEN

Androgen receptor (AR) is a validated therapeutic target for the treatment of metastatic castration-resistant prostate cancer (mCRPC). We report herein our design, synthesis, and biological characterization of highly potent small-molecule proteolysis targeting chimera (PROTAC) AR degraders using a potent AR antagonist and E3 ligase ligands with weak binding affinities to VHL protein. Our study resulted in the discovery of 11 (ARD-266), which effectively induces degradation of AR protein in AR-positive (AR+) LNCaP, VCaP, and 22Rv1 prostate cancer cell lines with DC50 values of 0.2-1 nM. ARD-266 is capable of reducing the AR protein level by >95% in these AR+ prostate cancer cell lines and effectively reduces AR-regulated gene expression suppression. For the first time, we demonstrated that an E3 ligand with micromolar binding affinity to its E3 ligase complex can be successfully employed for the design of highly potent and efficient PROTAC degraders and this finding may have a significant implication for the field of PROTAC research.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Descubrimiento de Drogas , Piperidinas/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Proteolisis/efectos de los fármacos , Receptores Androgénicos/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Antagonistas de Receptores Androgénicos/química , Proliferación Celular , Diseño de Fármacos , Humanos , Ligandos , Masculino , Piperidinas/química , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Receptores Androgénicos/química , Bibliotecas de Moléculas Pequeñas/química , Células Tumorales Cultivadas , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo
9.
Drugs ; 79(16): 1813-1818, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31605368

RESUMEN

Darolutamide (NUBEQA™) is a structurally distinct non-steroidal androgen receptor antagonist being developed by Orion and Bayer as a treatment for prostate cancer. Based on positive results in the phase III ARAMIS trial, darolutamide was recently approved in the USA for the treatment of men with non-metastatic castration-resistant prostate cancer. This article summarizes the milestones in the development of darolutamide leading to this first approval.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Antineoplásicos/farmacología , Aprobación de Drogas , Neoplasias de la Próstata/tratamiento farmacológico , Pirazoles/farmacología , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/química , Antineoplásicos/química , Ensayos Clínicos Fase III como Asunto , Humanos , Masculino , Pirazoles/química , Estados Unidos
10.
Sci Rep ; 9(1): 15008, 2019 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-31628408

RESUMEN

Patient-derived explant (PDE) culture of solid tumors is increasingly being applied to preclinical evaluation of novel therapeutics and for biomarker discovery. In this technique, treatments are added to culture medium and penetrate the tissue via a gelatin sponge scaffold. However, the penetration profile and final concentrations of small molecule drugs achieved have not been determined to date. Here, we determined the extent of absorption of the clinical androgen receptor antagonist, enzalutamide, into prostate PDEs, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and matrix-assisted laser/desorption ionisation (MALDI) mass spectrometry imaging (MSI). In a cohort of 11 PDE tissues from eight individual patients, LC-MS/MS quantification of PDE homogenates confirmed enzalutamide (10 µM) uptake by all PDEs, which reached maximal average tissue concentration of 0.24-0.50 ng/µg protein after 48 h culture. Time dependent uptake of enzalutamide (50 µM) in PDEs was visualized using MALDI MSI over 24-48 h, with complete penetration throughout tissues evident by 6 h of culture. Drug signal intensity was not homogeneous throughout the tissues but had areas of markedly high signal that corresponded to drug target (androgen receptor)-rich epithelial regions of tissue. In conclusion, application of MS-based drug quantification and visualization in PDEs, and potentially other 3-dimensional model systems, can provide a more robust basis for experimental study design and interpretation of pharmacodynamic data.


Asunto(s)
Absorción Fisicoquímica , Antagonistas de Receptores Androgénicos/química , Antineoplásicos/química , Evaluación Preclínica de Medicamentos/métodos , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata/patología , Espectrometría de Masas en Tándem/métodos , Anciano , Células Cultivadas , Cromatografía Liquida , Estudios de Cohortes , Humanos , Masculino , Persona de Mediana Edad , Feniltiohidantoína/química , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción
11.
Bioorg Med Chem ; 27(20): 115081, 2019 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-31493989

RESUMEN

Prostate cancer (PCa) is a major cause of cancer-related male death in worldwide. To develop of potential anti-prostate cancer agents, 22 kinds of 4-Amino-2H-benzo[h]chromen-2-one analogs were designed and synthesized as potent androgen receptor (AR) antagonist through rational drug modification leading to the discovery of a series of novel antiproliferative compounds. Analogs (3, 4, 5, 7, 8, 10, 11, 12, 16, 18, 21, 23, and 24) exhibited potent antagonistic potency against AR (inhibition >50%), and exhibited potent AR binding affinities as well as displayed the higher activities than finasteride toward LNCaP cells (AR-rich) versus PC-3 cells (AR-deficient). Moreover, the docking study suggested that the most potent antagonist 23 mainly bind to AR ligand binding pocket (LBP) site through Van der Waals' force interactions. The structure-activity relationship (SAR) of these designed 4-Amino-2H-benzo[h]chromen-2-one analogs was rationally explored and discussed. Collectively, this work provides a potential lead compound for anticancer agent development related to prostate cancer therapy, and took a step forward towards the development of novel and improved AR antagonists.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Antineoplásicos/farmacología , Simulación del Acoplamiento Molecular , Piperazina/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/síntesis química , Antagonistas de Receptores Androgénicos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Polarización de Fluorescencia , Humanos , Masculino , Estructura Molecular , Piperazina/química , Neoplasias de la Próstata/patología , Receptores Androgénicos/genética , Relación Estructura-Actividad , Células Tumorales Cultivadas
12.
J Food Biochem ; 43(9): e12987, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31489669

RESUMEN

The preventive effects of purple rice crude ethanolic extract (PRE) were firstly investigated on testosterone-induced benign prostatic hyperplasia (BPH) in castrated rats. As compared to vehicle-treated rats, lower prostate weights were found in the BPH rats that received PRE 1 g/kg bw. In addition, the PRE treatment down-regulated the androgen receptor (AR) expression in the dorsolateral prostate of those rats. In human prostate cancer cell line, LNCaP, PRE could reduce the cell growth, down-regulate the expression of AR and suppress prostate-specific antigen (PSA) secretion. Moreover, PRE also inhibited an activity of 5α-reductase from rat liver microsomes and the mutagenicity of Salmonella Typhimurium induced by standard mutagen. These results demonstrate that PRE altered testosterone-induced BPH in rats and retarded prostate cancer cell growth by modulating AR expression. It is therefore recommended that further investigation is undertaken into the chemopreventive potential of PRE in androgen-AR mediated diseases. PRACTICAL APPLICATIONS: This study revealed the mechanisms of purple rice extract on testosterone-induced rat benign prostatic hyperplasia. Such information, purple rice components show promise as an effective chemopreventive agent for prostatic hyperplasia prevention by alternating the influence of testosterone through its receptor. Thus, purple rice might be developed as food supplement for reduction of prostatic hyperplasia or cancer in elder men.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Oryza/química , Extractos Vegetales/farmacología , Hiperplasia Prostática/inducido químicamente , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/metabolismo , Testosterona/toxicidad , Antagonistas de Receptores Androgénicos/química , Animales , Colestenona 5 alfa-Reductasa/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Extractos Vegetales/química , Hiperplasia Prostática/tratamiento farmacológico , Ratas Wistar
13.
Assay Drug Dev Technol ; 17(8): 364-386, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31502857

RESUMEN

Prostate cancer is the leading cause of cancer and second leading cause of cancer-related death in men in the United States. Twenty percent of patients receiving the standard of care androgen deprivation therapy (ADT) eventually progress to metastatic and incurable castration-resistant prostate cancer (CRPC). Current FDA-approved drugs for CRPC target androgen receptor (AR) binding or androgen production, but only provide a 2- to 5-month survival benefit due to the emergence of resistance. Overexpression of AR coactivators and the emergence of AR splice variants, both promote continued transcriptional activation under androgen-depleted conditions and represent drug resistance mechanisms that contribute to CRPC progression. The AR contains two transactivation domains, activation function 2 (AF-2) and activation function 1 (AF-1), which serve as binding surfaces for coactivators involved in the transcriptional activation of AR target genes. Full-length AR contains both AF-2 and AF-1 surfaces, whereas AR splice variants only have an AF-1 surface. We have recently prosecuted a high-content screening campaign to identify hit compounds that can inhibit or disrupt the protein-protein interactions (PPIs) between AR and transcriptional intermediary factor 2 (TIF2), one of the coactivators implicated in CRPC disease progression. Since an ideal inhibitor/disruptor of AR-coactivator PPIs would target both the AF-2 and AF-1 surfaces, we describe here the development and validation of five AF-2- and three AF-1-focused assays to interrogate and prioritize hits that disrupt both transactivation surfaces. The assays were validated using a test set of seven known AR modulator compounds, including three AR antagonists and one androgen synthesis inhibitor that are FDA-approved ADTs, two investigational molecules that target the N-terminal domain of AR, and an inhibitor of the Hsp90 (heat shock protein) molecular chaperone.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Chaperonas Moleculares/farmacología , Receptores Androgénicos/metabolismo , Activación Transcripcional/efectos de los fármacos , Antagonistas de Receptores Androgénicos/química , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Chaperonas Moleculares/química , Células PC-3 , Relación Estructura-Actividad , Células Tumorales Cultivadas
14.
J Phys Chem B ; 123(36): 7657-7666, 2019 09 12.
Artículo en Inglés | MEDLINE | ID: mdl-31431014

RESUMEN

Androgen receptor (AR) is a steroid hormone nuclear receptor which upon binding its endogenous androgenic ligands (agonists), testosterone and dihydrotestosterone (DHT), alters gene transcription, producing a diverse range of biological effects. Antiandrogens, such as the pharmaceuticals bicalutamide and hydroxyflutamide, act as agonists in the absence of androgens and as antagonists in their presence or in high concentration. The atomic level mechanism of action by agonists and antagonists of AR is less well characterized. Therefore, in this study, multiple 1 µs molecular dynamics (MD), docking simulations, and perturbation-response analyses were performed to more fully explore the nature of interaction between agonist or antagonist and AR and the conformational changes induced in the AR upon interaction with different ligands. We characterized the mechanism of the ligand entry/exit and found that helix-12 and nearby structural motifs respond dynamically in that process. Modeling showed that the agonist and antagonist/agonist form a hydrogen bond with Thr877/Asn705 and that this interaction is absent for antagonists. Agonist binding to AR increases the mobility of residues at allosteric sites and coactivator binding sites, while antagonist binding decreases mobility at these important sites. A new site was also identified as a potential surface for allosteric binding. These results shed light on the effect of agonists and antagonists on the structure and dynamics of AR.


Asunto(s)
Antagonistas de Receptores Androgénicos/química , Andrógenos/química , Simulación de Dinámica Molecular , Antagonistas de Receptores Androgénicos/farmacología , Andrógenos/farmacología , Anilidas/química , Anilidas/farmacología , Sitios de Unión/efectos de los fármacos , Dihidrotestosterona/química , Dihidrotestosterona/farmacología , Flutamida/análogos & derivados , Flutamida/química , Flutamida/farmacología , Humanos , Nitrilos/química , Nitrilos/farmacología , Receptores Androgénicos/metabolismo , Testosterona/química , Testosterona/farmacología , Compuestos de Tosilo/química , Compuestos de Tosilo/farmacología
15.
J Enzyme Inhib Med Chem ; 34(1): 1597-1606, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31469015

RESUMEN

Prostate cancer (PCa) is the second leading cause of death in men. Apart from androgen receptor, 5α-reductase has also been recognized as a potential target. In this study, a series of androst-17ß-amide compounds have been designed and synthesized targeting both AR and 5α-reductase. Their anti-proliferation activities were evaluated in AR + cell line 22RV1 and AR - cell line PC-3. The results indicated that most of the synthesized compounds inhibited the testosterone-stimulated cell proliferation with good selectivity and safety. Among all the compounds, androst[3,2-c]pyrazole derivatives (9a-9d) displayed the best inhibition activity comparable with flutamide. Moreover, most of the synthesized compounds displayed good 5α-reductase inhibitory activities with IC50 lower than 1 µM. The docking result of 9d-AR indicated that AR was forced to expands its binding cavity and maintain an antagonistic conformation since the steric hindrance of 9d impeded H12 transposition. Overall, compound 9d can be identified as a potential dual 5α-reductase inhibitor and AR antagonist, which might be of therapeutic importance for PCa treatment.


Asunto(s)
Inhibidores de 5-alfa-Reductasa/farmacología , Antagonistas de Receptores Androgénicos/farmacología , Androstenos/farmacología , Colestenona 5 alfa-Reductasa/metabolismo , Diseño de Fármacos , Receptores Androgénicos/metabolismo , Inhibidores de 5-alfa-Reductasa/síntesis química , Inhibidores de 5-alfa-Reductasa/química , Antagonistas de Receptores Androgénicos/síntesis química , Antagonistas de Receptores Androgénicos/química , Androstenos/síntesis química , Androstenos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Células PC-3 , Relación Estructura-Actividad , Células Tumorales Cultivadas
16.
Eur J Med Chem ; 182: 111608, 2019 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-31437779

RESUMEN

Androgen receptor (AR) has been a target of prostate cancer (PC) for nearly six decades. Recently, downregulating or degrading AR and the mutants especially the splice variant 7 (AR-V7) lacking ligand binding domain (LBD) emerged as an advantageous therapeutic approach to overcome drug resistance. Here, the structural modification of darolutamide resulted in the discovery of dual-action AR inhibitors and down-regulators. Unlike other traditional AR antagonists targeting the AR-LBD, compounds 4k and 4b not only inhibit the activities of wt-AR and AR-F876L mutant but also downregulate the protein expression of full-length (AR-full) and AR variant 7 (AR-V7) at mRNA level. In cell proliferation assays, compounds 4k and 4b exhibited better antiproliferative activities than darolutamide and enzalutamide against AR-V7-positive 22Rv1 cells and VCaP cells. In addition, 4k demonstrated better antitumor activity than clinically used enzalutamide in castration-resistant VCaP xenograft model. Collectively, combining the activities of AR inhibition and downregulation, compound 4k is proposed as an advantageous lead compound to disrupt AR signaling and overcome resistance.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Antineoplásicos/farmacología , Regulación hacia Abajo/efectos de los fármacos , Descubrimiento de Drogas , Pirazoles/farmacología , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/síntesis química , Antagonistas de Receptores Androgénicos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Moleculares , Estructura Molecular , Mutación , Pirazoles/síntesis química , Pirazoles/química , Receptores Androgénicos/genética , Relación Estructura-Actividad
17.
Comb Chem High Throughput Screen ; 22(5): 307-316, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31267866

RESUMEN

AIM AND OBJECTIVE: To study the structural difference, optimization, molecular docking and development of new benzoyl amino phenoxy phenol derivatives as anti-prostate cancer agents. MATERIALS AND METHODS: Strategies towards the identification of novel benzoyl amino phenoxy phenol (BAPP), molecular docking was performed with the designed Androgen Receptor (AR) blockers. Pharmacophore-based studies revealed that the nitro- or cyano-substituted anilide groups have influenced the activity profiles of non-steroidal AR antagonists, followed by the molecular docking studies with five AR receptors. Molecular docking studies were carried out using Maestro from Schrödinger. Absorption, Distribution, Metabolism, and Excretion (ADME) properties of the BAPP derivatives were evaluated for the predictive bioavailability/drug-likeness. These studies supported vital information for designing new anti-prostate cancer agents. RESULTS AND DISCUSSION: There are 125 compounds were screened and best fit compounds (12 entries) were well-synthesized in good to excellent yields and anticancer activities were evaluated. The compounds, 6i showed the highest activities of this series (14.65 ± 1.35 µM). CONCLUSION: The present approach is simple and efficient for the synthesis of BAPP derivatives and the observed IC50 values of BAPPs were in good agreement with the glide scores obtained from the molecular docking. We, further, intend to carry out in vitro and in vivo AR binding studies for the active compounds.


Asunto(s)
Antagonistas de Receptores Androgénicos/química , Antineoplásicos/química , Simulación del Acoplamiento Molecular , Fenol/farmacología , Simulación por Computador , Diseño de Fármacos , Humanos , Masculino , Fenol/síntesis química , Neoplasias de la Próstata/tratamiento farmacológico
18.
J Med Chem ; 62(14): 6751-6764, 2019 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-31274313

RESUMEN

Structure-based modification of mifepristone (1) led to the discovery of novel mifepristone derivatives with improved selectivity profile. Addition of a methyl group at the C10 position of the steroid has a significant impact on progesterone receptor (PR) and androgen receptor (AR) activity. Within this series, OP-3633 (15) emerged as a glucocorticoid receptor (GR) antagonist with increased selectivity against PR and AR, improved cytochrome P450 inhibition profile, and significantly improved pharmacokinetic properties compared to 1. Furthermore, 15 demonstrated substantial inhibition of GR transcriptional activity in the GR positive HCC1806 triple negative breast cancer xenograft model. Overall, compound 15 is a promising GR antagonist candidate to clinically evaluate the impact of GR inhibition in reversal or prevention of therapy resistance.


Asunto(s)
Mifepristona/análogos & derivados , Mifepristona/farmacología , Receptores de Glucocorticoides/antagonistas & inhibidores , Antagonistas de Receptores Androgénicos/química , Antagonistas de Receptores Androgénicos/farmacología , Descubrimiento de Drogas , Humanos , Modelos Moleculares , Receptores Androgénicos/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Progesterona/antagonistas & inhibidores , Receptores de Progesterona/metabolismo
19.
Int J Cancer ; 145(5): 1382-1394, 2019 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-30828788

RESUMEN

Darolutamide is a novel androgen receptor (AR) antagonist with a distinct chemical structure compared to other AR antagonists and currently in clinical Phase 3 trials for prostate cancer. Using cell-based transactivation assays, we demonstrate that darolutamide, its diastereomers and its main metabolite keto-darolutamide are strong, competitive antagonists for AR wild type, and also for several mutants identified in prostate cancer patients for which other AR antagonists show reduced antagonism or even agonism. Darolutamide, its two diastereomers and main metabolite are also strong antagonists in assays measuring AR N/C interaction and homodimerization. Molecular modeling suggests that the flexibility of darolutamide allows accommodation in the W742C/L mutated AR ligand-binding pocket while for enzalutamide the loss of the important hydrophobic interaction with W742 leads to reduced AR interaction. This correlates with an antagonistic pattern profile of coregulator recruitment for darolutamide. In vitro efficacy studies performed with androgen-dependent prostate cancer cell lines show that darolutamide strongly reduces cell viability and potently inhibits spheroid formation. Also, a marked down-regulation of androgen target genes paralleled by decreased AR binding to gene regulatory regions is seen. In vivo studies reveal that oral dosing of darolutamide markedly reduces growth of the LAPC-4 cell line-derived xenograft and of the KuCaP-1 patient-derived xenograft. Altogether, these results substantiate a unique antagonistic profile of darolutamide and support further development as a prostate cancer drug.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Pirazoles/farmacología , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/química , Animales , Línea Celular Tumoral , Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones SCID , Modelos Moleculares , Neoplasias de la Próstata Resistentes a la Castración/genética , Dominios Proteicos , Pirazoles/química , Receptores Androgénicos/química , Receptores Androgénicos/genética , Ensayos Antitumor por Modelo de Xenoinjerto
20.
Nucleic Acids Res ; 47(8): 3828-3835, 2019 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-30838415

RESUMEN

The crucial role of androgen receptor (AR) in prostate cancer development is well documented, and its inhibition is a mainstay of prostate cancer treatment. Here, we analyze the perturbations to the AR cistrome caused by a minor groove binding molecule that is designed to target a sequence found in a subset of androgen response elements (ARE). We find treatment with this pyrrole-imidazole (Py-Im) polyamide exhibits sequence selectivity in its repression of AR binding in vivo. Differentially changed loci are enriched for sequences resembling ARE half-sites that match the Py-Im polyamide binding preferences determined in vitro. Comparatively, permutations of the ARE half-site bearing single or double mismatches to the Py-Im polyamide binding sequence are not enriched. This study confirms that the in vivo perturbation pattern caused by a sequence specific polyamide correlates with its in vitro binding preference genome-wide in an unbiased manner.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Antineoplásicos/farmacología , Imidazoles/farmacología , Nylons/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Pirroles/farmacología , Receptores Androgénicos/genética , Antagonistas de Receptores Androgénicos/química , Antagonistas de Receptores Androgénicos/metabolismo , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Secuencia de Bases , Sitios de Unión , Línea Celular Tumoral , Dihidrotestosterona/farmacología , Expresión Génica , Humanos , Imidazoles/química , Imidazoles/metabolismo , Masculino , Ratones , Ratones SCID , Nylons/química , Nylons/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Pirroles/química , Pirroles/metabolismo , Receptores Androgénicos/metabolismo , Elementos de Respuesta , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
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