mdv-3100 and Prostatic-Neoplasms

Prostate cancer is the most common carcinoma of the male urinary system in developed countries. Androgen deprivation therapy has been commonly used in the treatment of prostate cancer for decades, but most patients will inevitably develop into more aggressive castration-resistant prostate cancer. Therefore, novel strategies are urgent to address this resistance mechanism. In this review, we discussed some new strategies for targeting androgen receptors through degradation pathways as potential treatments for prostate cancer.

Topics: Androgen Receptor Antagonists; Animals; Antineoplastic Agents; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Heat-Shock Proteins; Humans; Male; Prostatic Neoplasms; Proteolysis; Receptors, Androgen; Signal Transduction; Thiohydantoins; Ubiquitination

Metastatic prostate cancer is treated with drugs that antagonize androgen action, but most patients progress to a more aggressive form of the disease called castration-resistant prostate cancer, driven by elevated expression of the androgen receptor. Here we characterize the diarylthiohydantoins RD162 and MDV3100, two compounds optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased androgen receptor expression. Both compounds bind to the androgen receptor with greater relative affinity than the clinically used antiandrogen bicalutamide, reduce the efficiency of its nuclear translocation, and impair both DNA binding to androgen response elements and recruitment of coactivators. RD162 and MDV3100 are orally available and induce tumor regression in mouse models of castration-resistant human prostate cancer. Of the first 30 patients treated with MDV3100 in a Phase I/II clinical trial, 13 of 30 (43%) showed sustained declines (by >50%) in serum concentrations of prostate-specific antigen, a biomarker of prostate cancer. These compounds thus appear to be promising candidates for treatment of advanced prostate cancer.

Topics: Androgen Antagonists; Anilides; Animals; Antineoplastic Agents; Benzamides; Biological Availability; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; DNA; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Receptors, Androgen; Tosyl Compounds; Transcription, Genetic; Xenograft Model Antitumor Assays

Androgen receptor (AR) antagonists have been widely used for the treatment of prostate cancer (PCa). As a link between the AR and its transcriptional function, the activation function 2 (AF2) region has recently been revealed as a novel targeting site for developing AR antagonists. Here, we reported a series of

Topics: Androgen Receptor Antagonists; Animals; Antineoplastic Agents; Binding Sites; Cell Proliferation; Gene Expression; Humans; Male; Mice, SCID; Molecular Docking Simulation; Molecular Structure; Prostatic Neoplasms; Protein Transport; Receptors, Androgen; Structure-Activity Relationship; Sulfonamides; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Indazoles; Male; Molecular Structure; Prostatic Neoplasms; Skeleton; Structure-Activity Relationship; Triazoles

The androgen receptor (AR) antagonists are efficient therapeutics for the treatment of prostate cancer (PCa). All the approved AR antagonists to date are targeted to the ligand-binding pocket (LBP) of AR and have suffered from various drug resistances, whereas AR antagonist targeting non-LBP site of AR is conceived as a promising strategy. Through the scaffold hopping of AR LBP antagonists, the 2-chloro-4-(1

Topics: Acetamides; Androgen Antagonists; Androgen Receptor Antagonists; Cell Line, Tumor; Cell Proliferation; Humans; Ligands; Male; Prostatic Neoplasms; Pyrazoles; Receptors, Androgen

Prostate cancer (PC) is the most common malignancy in men worldwide. Here, two series of novel thiohydantoin derivatives of enzalutamide as potent androgen receptor (AR) antagonists were designed and synthesized. Among them, compound 31c was identified as an AR antagonist which is 2.3-fold more potent than enzalutamide. Molecular docking studies were performed to explain the improved potency of 31c at AR. In cell proliferation assays, 31c exhibited similar anti-proliferative activities with enzalutamide against hormone sensitive LNCaP cells and AR-overexpressing LNCaP/AR cells. These data indicate that 31c can be a good lead compound for further structure optimization for the treatment of prostate cancer.

Topics: Androgen Receptor Antagonists; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Male; Models, Molecular; Molecular Structure; Prostatic Neoplasms; Structure-Activity Relationship; Thiohydantoins

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

Topics: Androgen Receptor Antagonists; Animals; Biotransformation; Cell Line, Tumor; Dogs; Drug Discovery; Drug Resistance, Neoplasm; Hepatocytes; Humans; Male; Models, Molecular; Mutation; Nitriles; Picolines; Piperidines; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Pyridines; Rats; Spiro Compounds; Structure-Activity Relationship

The androgen receptor (AR) is a pivotal target for the treatment of prostate cancer (PC) even when the disease progresses toward androgen-independent or castration-resistant forms. In this study, a series of sulfoxide derivatives were prepared and their antiproliferative activity evaluated in vitro against four different human prostate cancer cell lines (22Rv1, DU-145, LNCaP and VCap). Bicalutamide and enzalutamide were used as positive controls. Compound 28 displayed significant enhancement in anticancer activity across the four PC cell lines with IC

Topics: Anilides; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Male; Models, Molecular; Molecular Structure; Nitriles; Prostatic Neoplasms; Structure-Activity Relationship; Sulfoxides; Tosyl Compounds

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.

Topics: Androgen Receptor Antagonists; Animals; Cell Line, Tumor; Cell Survival; Drug Design; Drug Evaluation, Preclinical; Half-Life; Humans; Male; Prostatic Neoplasms; Proteolysis; Rats; Rats, Sprague-Dawley; Receptors, Androgen; Structure-Activity Relationship; Survival Rate; Transplantation, Heterologous; Zebrafish

Prostate cancer (PCa) is one of the most common malignancies affecting men worldwide. Androgen receptor (AR) has been a target of PCa treatment for nearly six decades. AR antagonists/degraders can effectively treat PCa caused by increased AR overexpression. However, all approved AR antagonists have similar chemical structures and exhibit the same mode of action on the protein. Although initially effective, resistance to these AR antagonists usually develops. Therefore, this calls for the identification of novel chemical structures of AR antagonists to overcome the resistance. Herein, we employed the synergetic combination of virtual and experimental screening to identify a flavonoid compound which not only effectively inhibits AR transcriptional activity, but also induces the degradation of the protein. Based on this compound, we designed and synthesized a series of derivatives. We discovered that the most potent compound 10e could effectively inhibit AR transcriptional activity, and possessed a profound ability to cause degradation of both full length- and ARv7 truncated forms of human AR. Notably, 10e efficiently inhibited the growth of ARv7 dependent prostate cancer cell-lines, which are completely resistant to all current anti-androgens. Compound 10e also showed strong antitumor activity in the LNCaP (androgen dependent prostate cancer cell line) in vivo xenograft model. These results provide a foundation for the development of a new class of AR antagonists.

Topics: Androgen Receptor Antagonists; Antineoplastic Agents; Apoptosis; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Flavonoids; Humans; Male; Molecular Structure; Prostatic Neoplasms; Receptors, Androgen; Structure-Activity Relationship; Tumor Cells, Cultured

A series of propanamide derivatives were designed, synthesized, and pharmacologically characterized as selective androgen receptor degraders (SARDs) and pan-antagonists that exert a broad-scope androgen receptor (AR) antagonism. Incorporating different basic heteromonocyclic B-ring structural elements in the common A-ring-linkage-B-ring nonsteroidal antiandrogen general pharmacophore contributed to a novel scaffold of small molecules with SARD and pan-antagonist activities even compared to our recently published AF-1 binding SARDs such as UT-69 (

Topics: Amides; Androgen Receptor Antagonists; Animals; Antineoplastic Agents; Benzamides; Cell Proliferation; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; HEK293 Cells; Humans; Male; Mice; Molecular Structure; Neoplasms, Experimental; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Rats; Rats, Sprague-Dawley; Receptors, Androgen; Structure-Activity Relationship

As a continuation of our research on developing potent and potentially safe androgen receptor (AR) degrader, a series of novel proteolysis targeting chimeras (PROTACs) containing the phthalimide degrons with different linker were designed, synthesized and evaluated for their AR degradation activity against LNCaP (AR+) cell line. Most of the synthesized compounds displayed moderate to satisfactory AR binding affinity and might lead to antagonist activity against AR. Among them, compound A16 exhibited the best AR binding affinity (85%) and degradation activity against AR. Due to the strong fluorescence properties of pomalidomide derivatives, B10 was found to be effectively internalized and visualized in LNCaP (AR + ) cells than PC-3 (AR-) cells. Moreover, the molecular docking of A16 with AR and the active site of DDB1-CRBN E3 ubiquitin ligase complex provides guidance to design new PROTAC degrons targeting AR for prostate cancer therapy. These results represent a step toward the development of novel and improved AR PROTACs.

Topics: Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Male; Models, Molecular; Molecular Structure; Prostatic Neoplasms; Proteolysis; Receptors, Androgen; Structure-Activity Relationship

Proteolysis targeting chimera (PROTAC) small-molecule degraders have emerged as a promising new type of therapeutic agents, but the design of PROTAC degraders with excellent oral pharmacokinetics is a major challenge. In this study, we present our strategies toward the discovery of highly potent PROTAC degraders of androgen receptor (AR) with excellent oral pharmacokinetics. Employing thalidomide to recruit cereblon/cullin 4A E3 ligase and through the rigidification of the linker, we discovered highly potent AR degraders with good oral pharmacokinetic properties in mice with ARD-2128 being the best compound. ARD-2128 achieves 67% oral bioavailability in mice, effectively reduces AR protein and suppresses AR-regulated genes in tumor tissues with oral administration, leading to the effective inhibition of tumor growth in mice without signs of toxicity. This study supports the development of an orally active PROTAC AR degrader for the treatment of prostate cancer and provides insights and guidance into the design of orally active PROTAC degraders.

Topics: Administration, Oral; Androgen Receptor Antagonists; Animals; Antineoplastic Agents; Area Under Curve; Biological Availability; Drug Delivery Systems; Drug Discovery; Half-Life; Humans; Injections, Intravenous; Male; Mice; Microsomes, Liver; Molecular Structure; Prostatic Neoplasms; Receptors, Androgen; Structure-Activity Relationship; Xenograft Model Antitumor Assays

Pragmatic insertion of pargyline, a LSD1 inhibitor, as a surface recognition part in the HDAC inhibitory pharmacophore was planned in pursuit of furnishing potent antiprostate cancer agents. Resultantly, compound

Topics: Antineoplastic Agents; Histone Deacetylase Inhibitors; Histone Demethylases; Humans; Male; Pargyline; Prostatic Neoplasms

We report herein the design, synthesis, and pharmacological characterization of a library of novel aryl pyrazol-1-yl-propanamides as selective androgen receptor degraders (SARDs) and pan-antagonists that exert broad-scope AR antagonism. Pharmacological evaluation demonstrated that introducing a pyrazole moiety as the B-ring structural element in the common A-ring-linkage-B-ring nonsteroidal antiandrogens' general pharmacophore allowed the development of a new scaffold of small molecules with unique SARD and pan-antagonist activities even compared to our recently published AF-1 binding SARDs such as UT-155 (

Topics: Androgen Receptor Antagonists; Animals; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Resistance, Neoplasm; Half-Life; Humans; Male; Mice; Microsomes, Liver; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Androgen; Structure-Activity Relationship; Xenograft Model Antitumor Assays

A novel scaffold of arylpiperazine derivatives was discovered as potent androgen receptor (AR) antagonist through rational drug designation based on our pre-work, leading to the discovery of a series of new antiproliferative compounds. Compounds 10, 16, 27, 29 and 31 exhibited relatively strong antagonistic potency against AR and exhibited potent AR binding affinities, while compounds 5, 6, 10, 14, 16, 19, 21, 27 and 31 exhibited strong cytotoxic activities against LNCaP cells (AR-rich) as well as also displayed the higher activities than finasteride toward PC-3 (AR-deficient) and DU145 (AR-deficient). Docking study suggested that the most potent antagonist 16 mainly bind to AR ligand binding pocket (LBP) site through hydrogen bonding interactions. The structure-activity relationship (SAR) of these designed arylpiperazine derivatives was rationally explored and discussed. These results indicated that the novel scaffold compounds demonstrated a step towards the development of novel and improved AR antagonists, and promising candidates for future development were identified.

Topics: Androgen Receptor Antagonists; Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Humans; Male; Molecular Docking Simulation; Molecular Structure; Piperazines; Prostatic Neoplasms; Receptors, Androgen; Structure-Activity Relationship

In our effort to find small-molecule treatments of advanced prostate cancers (PCs), a novel series of indolyl and indolinyl propanamides (series II and III) were discovered as selective androgen receptor degraders (SARDs). Initial studies of androgen receptor (AR) antagonist (1) and agonist (2) propanamides yielded a tertiary aniline (3) with novel SARD activity but poor metabolic stability. Cyclization to II and III produced submicromolar AR antagonism and protein degradation selective to AR and AR splice variant (AR SV). II and III maintained potency against enzalutamide-resistant (Enz-R) mutant ARs and PC cells and were efficacious in Enz-R xenografts, suggesting their potential to treat advanced PCs. Design, synthesis, and biological activity of novel SARDs that could potentially be used for the treatment of a wide spectrum of PCs including castration-resistant, Enz-R, and/or AR SV-dependent advanced PCs that are often untreatable with known hormone therapies are discussed.

Topics: Amides; Androgen Receptor Antagonists; Androgens; Animals; Benzamides; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Resistance, Neoplasm; Humans; Indoles; Male; Mice; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Proteolysis; Rats; Receptors, Androgen; Structure-Activity Relationship; Xenograft Model Antitumor Assays

Prostate cancer (PCa) is the most frequently diagnosed male malignant tumor and remains the second leading cause of male cancer mortality in the western countries. The second-generation antiandrogen enzalutamide (ENZa) can prolong survival time for patients with mCRPC. However, the overexpression of glucocorticoids receptor (GR) in mCRPC cells causes the resistance of antiandrogen and leads to the failure of androgen receptor (AR) targeting therapy. Herein, based on the chemical structures of antiandrogen and crystal structure of GR, we set up to develop GR/AR (GR and AR) dual antagonist by virtual screening and biological evaluation. We identified Z19 as a dual AR/GR antagonist. Z19 inhibited the transcription activity of both AR and GR, reducing both protein and mRNA level of the downstream proteins of GR and AR signaling, and provided a potential lead compound for the development of novel treatment agents of prostate cancer. Our work demonstrates that rational drug design is an efficient strategy in development of the GR/AR dual antagonist for the treatment of prostate cancer.

Topics: Androgen Receptor Antagonists; Cell Proliferation; Drug Design; Humans; Male; Molecular Docking Simulation; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Protein Conformation; Receptors, Androgen; Receptors, Glucocorticoid; RNA, Messenger; Transcription, Genetic; User-Computer Interface

Deshydroxy propioanilides were synthesised by Michael addition reaction between substituted thiophenols onto four different phenylacrylamide derivatives to give twenty-three novel deshydroxy bicalutamide derivatives lacking the central hydroxyl group. The antiproliferative activities of these compounds were evaluated against human prostate cancer cell lines and thirteen compounds showed better inhibitory activities (IC

Topics: Androgen Antagonists; Anilides; Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Cell Proliferation; Drug Discovery; Drug Screening Assays, Antitumor; Humans; Male; Models, Molecular; Nitriles; Prostatic Neoplasms; Tosyl Compounds

The androgen receptor (AR) is a steroid hormone receptor and its high expression and disruption of its regulation are strongly implicated in prostate cancer (PCa) development. One of the current therapies includes application of steroidal antiandrogens leading to blockade of the AR action by the abrogation of AR-mediated signaling. We introduced here novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused steroidal compounds, described their synthesis based on [8π+2π] cycloaddition reactions of diazafulvenium methides with different steroidal scaffolds and showed their biological evaluation in different prostate cancer cell lines in vitro. Our results showed the ability of novel compounds to suppress the expression of known androgen receptor targets, Nkx3.1 and PSA in two prostate cell lines, 22Rv1 and VCaP. Candidate compound diminished the transcription of AR-regulated genes in the reporter cell line in a concentration-dependent manner. Antiproliferative activity of the most promising steroid was studied by clonogenic assay and induction of apoptosis in treated cells was documented by immunoblot detection of cleaved PARP.

Topics: Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Homeodomain Proteins; Humans; Male; Molecular Docking Simulation; Prostatic Neoplasms; Pyrazoles; Pyridines; Receptors, Androgen; Steroids; Transcription Factors

Prostate cancer is one of the main causes of male cancer-related deaths worldwide and the suppression of androgen receptor signalling is established as an effective strategy for the treatment. A series of galeterone analogues including several steroid-fused azacycles, as well as 17-(benzimidazol-1-ylimino), 16α-(benzimidazol-2-ylamino), and 16α-(benzothiazol-2-ylamino) steroid derivatives, were synthesized and tested against prostate cancer cell lines. Candidate compound 3f was shown to reduce AR-regulated transcription in a dose-dependent manner in nanomolar ranges and suppress expression of AR-regulated proteins Nkx3.1 and PSA in 22Rv1-ARE14 and VCaP cancer cell lines. Flexible docking study revealed similar position of 3f within AR binding site in comparison of galeterone even with stronger binding energy.

Topics: Androstadienes; Antineoplastic Agents; Benzimidazoles; Cell Line; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Male; Molecular Structure; PC-3 Cells; Prostatic Neoplasms; Structure-Activity Relationship

SAR studies on bicalutamide, enobosarm and enzalutamide analogues, functionalised with polyfluorinated groups, is presented. Among the novel bicalutamide and enobosarm derivatives synthesised, several displayed significantly improved in vitro anticancer activity, with IC

Topics: Anilides; Animals; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Cell Proliferation; CHO Cells; Cricetulus; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Ether-A-Go-Go Potassium Channels; Humans; Hydrocarbons, Fluorinated; Male; Mice; Mice, Nude; Molecular Structure; Neoplasms, Experimental; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Structure-Activity Relationship; Sulfhydryl Compounds; Tosyl Compounds

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.

Topics: Androgen Receptor Antagonists; Antineoplastic Agents; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Fluorescence Polarization; Humans; Male; Molecular Docking Simulation; Molecular Structure; Piperazine; Prostatic Neoplasms; Receptors, Androgen; Structure-Activity Relationship; Tumor Cells, Cultured

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

Topics: Androgen Receptor Antagonists; Cell Proliferation; Drug Design; Drug Discovery; Humans; Ligands; Male; Piperidines; Prostatic Neoplasms; Proteasome Endopeptidase Complex; Proteolysis; Receptors, Androgen; Small Molecule Libraries; Tumor Cells, Cultured; Ubiquitin; Ubiquitin-Protein Ligases; Von Hippel-Lindau Tumor Suppressor Protein

Prostate cancer (PC) is a major cause of cancer-related male death in worldwide and the identification of new and improved potent anti-PC molecules is constantly required. A novel scaffold of tetrahydroisoquinoline thiohydantoin was rationally designed based on the enzalutamide structures and our pre-work, leading to the discovery of a series of new antiproliferative compounds. Several new analogues displayed improved androgen receptor (AR) antagonistic activity, while maintaining the higher selective toxicity toward LNCaP cells (AR-rich) versus DU145 cells (AR-deficient) compared to enzalutamide. In fact, compound 55 exhibited promising in vitro antitumor activity by impairing AR unclear translocation. More importantly, 55 showed better pharmacokinetic properties compared to the compound 1 reported in our pre-work. These results demonstrate a step towards the development of novel and improved AR antagonists.

Topics: Androgen Receptor Antagonists; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Design; Humans; Male; Molecular Docking Simulation; Prostatic Neoplasms; Protein Conformation; Rats; Receptors, Androgen; Thiohydantoins

Several flavonoids and their biosynthetic precursor chalcones were designed and synthesized to improve the biological effects of the lead compound 2'-hydroxyflavonone against androgen receptor (AR)-dependent transcriptional stimulation. Newly synthesized chalcones 19 and 26 suppressed AR-dependent transcription as well as DHT-dependent growth stimulation at a low micromolar level. These compounds were also effective against ligand-independent constitutively active mutant AR derived from castration-resistant PCa (CRPC). Compounds 19 and 26 showed broad spectrum antiproliferative activity at 5-10 μM against multiple tumor cell lines including androgen-independent and taxane-resistant prostate cancer as well as a multidrug-resistant subline. Mode of action studies suggested that 19 induced sub-G1 accumulation in PC-3 cells by disrupting the microtubule network without affecting cell cycle progression. Furthermore, the in vivo effectiveness of chalcone 19 was confirmed in a xenograft model antitumor assay. Thus, chalcone 19 has the potential to be a bifunctional lead for treatment of AR-dependent PCa at lower doses as well as AR-independent PCa, including CRPC, at higher doses.

Topics: Androgen Receptor Antagonists; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Chalcones; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Flavonoids; Humans; Male; Mice; Mice, SCID; Molecular Structure; Neoplasms, Experimental; Prostatic Neoplasms; Receptors, Androgen; Structure-Activity Relationship

A novel scaffold of indoline thiohydantoin was discovered as potent androgen receptor (AR) antagonist through rational drug designation. Several compounds showed good biological profiles in AR binding and higher selective toxicity than enzalutamide toward LNCaP cells (AR-rich) versus DU145 cells (AR-deficient). In addition, the docking studies supported the rationalization of the biological evaluation. Among these compounds, the representative compound 48c exhibited the strongest inhibitory effect on LNCaP growth and also acted as a competitive AR antagonist. Further preliminary mechanism study confirmed that 48c exerted its AR antagonistic activity through impairing AR nuclear translocation. All these results indicated that the novel scaffold compounds demonstrated AR antagonistic behavior and promising candidates for future development were identified.

Topics: Active Transport, Cell Nucleus; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Cell Proliferation; Humans; Indoles; Male; Molecular Docking Simulation; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Receptors, Androgen; Thiohydantoins

Topics: 3T3 Cells; Acetanilides; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Computer Simulation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Heterocyclic Compounds, 3-Ring; Humans; Male; Mice; Mice, Inbred BALB C; Molecular Structure; Prostatic Neoplasms; Receptors, Androgen; Structure-Activity Relationship

Prostate cancer (PC) is the fifth leading cause of cancer death in men, and the androgen receptor (AR) represents the primary target for PC treatment, even though the disease frequently progresses toward androgen-independent forms. Most of the commercially available nonsteroidal antiandrogens show a common scaffold consisting of two aromatic rings connected by a linear or a cyclic spacer. By taking advantage of a facile, one-pot click chemistry reaction, we report herein the preparation of a small library of novel 1,4-substituted triazoles with AR antagonistic activity. Biological and theoretical evaluation demonstrated that the introduction of the triazole core in the scaffold of nonsteroidal antiandrogens allowed the development of small molecules with improved overall AR-antagonist activity. In fact, compound 14d displayed promising in vitro antitumor activity toward three different prostate cancer cell lines and was able to induce 60% tumor growth inhibition of the CW22Rv1 in vivo xenograft model. These results represent a step toward the development of novel and improved AR antagonists.

Topics: Animals; Cell Line, Tumor; Drug Discovery; Gene Expression Regulation, Neoplastic; Humans; Male; Mice, Nude; Models, Molecular; Nonsteroidal Anti-Androgens; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; RNA, Messenger; Triazoles

Prostate cancer is the most frequently diagnosed malignancy and the leading cause of cancer related death in men. First line therapy for disseminated disease relies on androgen deprivation, leveraging the addiction of these tumors on androgens for both growth and survival. Treatment typically involves antagonizing the androgen receptor (AR) or blocking the synthesis of androgens. Recurrence is common and within 2-3years patients develop castration resistant tumors that become unresponsive to AR-axis targeted therapies. In order to provide a more effective treatment, we are utilizing an approach that targets a key scaffolding protein, Sigma1 (also known as sigma-1 receptor), a unique 26-kilodalton integral membrane protein that is critical in stabilizing the AR. Herein we report on a new series of Sigma1 compounds for lead optimization derived from a hybrid pharmacophore approach.

Topics: Animals; ERG1 Potassium Channel; Guanidines; Half-Life; Humans; Male; Mice; Microsomes, Liver; Neoplasm Staging; Prostatic Neoplasms; Protein Binding; Receptors, sigma; Sigma-1 Receptor; Structure-Activity Relationship

The clinically used androgen receptor (AR) antagonists (bicalutamide, flutamide and nilutamide) bind with low affinity to AR and can induce escape mechanisms. Furthermore, under AR gene amplification or mutation conditions they demonstrate agonist activity and fail to inhibit AR, causing relapse into castration resistant prostate cancer (CRPC). Discovery of new scaffolds distinct from the 4-cyano/nitro-3-(trifluoromethyl)phenyl group common to currently used antiandrogens is urgently needed to avoid cross-resistance with these compounds. In this study, a series of twenty-nine 7-substituted umbelliferone derivatives was prepared and their antiproliferative activities were evaluated. The most active compound 7a demonstrated submicromolar inhibitory activity in the human prostate cancer cell line (22Rv1); IC50=0.93 μM which represents a 50 fold improvement over the clinical antiandrogen bicalutamide (IC50=46 μM) and a more than 30 fold improvement over enzalutamide (IC50=32 μM). Interestingly, this compound showed even better activity against the human breast cancer cell line (MCF-7); IC50=0.47 μM. Molecular modelling studies provided a plausible theoretical explanation for our findings.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Humans; Male; Models, Molecular; Molecular Structure; Prostatic Neoplasms; Receptors, Androgen; Structure-Activity Relationship; Umbelliferones

Prostate cancer (PC) is one of the major causes of male death worldwide and the development of new and more potent anti-PC compounds is a constant requirement. Among the current treatments, (R)-bicalutamide and enzalutamide are non-steroidal androgen receptor antagonist drugs approved also in the case of castration-resistant forms. Both these drugs present a moderate antiproliferative activity and their use is limited due to the development of resistant mutants of their biological target. Insertion of fluorinated and perfluorinated groups in biologically active compounds is a current trend in medicinal chemistry, applied to improve their efficacy and stability profiles. As a means to obtain such effects, different modifications with perfluoro groups were rationally designed on the bicalutamide and enzalutamide structures, leading to the synthesis of a series of new antiproliferative compounds. Several new analogues displayed improved in vitro activity towards four different prostate cancer cell lines, while maintaining full AR antagonism and therefore representing promising leads for further development. Furthermore, a series of molecular modelling studies were performed on the AR antagonist conformation, providing useful insights on potential protein-ligand interactions.

Topics: Anilides; Antineoplastic Agents; Benzamides; Caco-2 Cells; Cell Line, Tumor; Cell Proliferation; Chemistry Techniques, Synthetic; Drug Design; Drug Resistance, Neoplasm; Humans; Male; Microsomes, Liver; Molecular Docking Simulation; Molecular Dynamics Simulation; Nitriles; Permeability; Phenylthiohydantoin; Prostatic Neoplasms; Protein Conformation; Receptors, Androgen; Tosyl Compounds

Prostate cancer is a major cause of male death worldwide and the identification of new and improved treatments is constantly required. Among the available options, different non-steroidal androgen receptor (AR) antagonists are approved also to treat castration-resistant forms. Most of these drugs show limited application due to the development of resistant mutants of their biological target. Following docking-based studies on a homology model for the AR open antagonist conformation, a series of novel 3,5-bis-trifluoromethylphenyl compounds was designed with the aim to improve the antiproliferative activity of anti-androgen drugs bicalutamide and enzalutamide. The new structural modifications might impede the receptor to adopt its closed agonist conformation also in the presence of adaptive mutations. Among the novel compounds synthesised, several displayed significantly improved in vitro activity in comparison with the parent structures, with IC50 values in the low micromolar range against four different prostate cancer cell lines (LNCaP, VCaP, DU-145, 22Rv1). Selected hits demonstrated full AR antagonistic behaviour and promising candidates for further development were identified.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Male; Molecular Docking Simulation; Molecular Structure; Prostatic Neoplasms; Structure-Activity Relationship; Xylenes

While enzalutamide and abiraterone are approved for treatment of metastatic castration-resistant prostate cancer (mCRPC), approximately 20-40% of patients have no response to these agents. It has been stipulated that the lack of response and the development of secondary resistance to these drugs may be due to the presence of AR splice variants. HDAC6 has a role in regulating the androgen receptor (AR) by modulating heat shock protein 90 (Hsp90) acetylation, which controls the nuclear localization and activation of the AR in androgen-dependent and independent scenarios. With dual-acting AR-HDAC6 inhibitors it should be possible to target patients who don't respond to enzalutamide. Herein, we describe the design, synthesis and biological evaluation of dual-acting compounds which target AR and are also specific towards HDAC6. Our efforts led to compound 10 which was found to have potent dual activity (HDAC6 IC

Topics: Androgen Antagonists; Animals; Cell Line, Tumor; Crystallography, X-Ray; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Histone Deacetylases; HSP90 Heat-Shock Proteins; Humans; Male; Mice; Models, Molecular; Prostatic Neoplasms

The synthesis and in vitro and in vivo antibreast and antiprostate cancers activities of novel C-4 heteroaryl 13-cis-retinamides that modulate Mnk-eIF4E and AR signaling are discussed. Modifications of the C-4 heteroaryl substituents reveal that the 1H-imidazole is essential for high anticancer activity. The most potent compounds against a variety of human breast and prostate cancer (BC/PC) cell lines were compounds 16 (VNHM-1-66), 20 (VNHM-1-81), and 22 (VNHM-1-73). In these cell lines, the compounds induce Mnk1/2 degradation to substantially suppress eIF4E phosphorylation. In PC cells, the compounds induce degradation of both full-length androgen receptor (fAR) and splice variant AR (AR-V7) to inhibit AR transcriptional activity. More importantly, VNHM-1-81 has strong in vivo antibreast and antiprostate cancer activities, while VNHM-1-73 exhibited strong in vivo antibreast cancer activity, with no apparent host toxicity. Clearly, these lead compounds are strong candidates for development for the treatments of human breast and prostate cancers.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Movement; Cell Proliferation; Dose-Response Relationship, Drug; Eukaryotic Initiation Factor-4E; Humans; Male; MCF-7 Cells; Mice; Mice, Nude; Mice, SCID; Molecular Structure; Prostatic Neoplasms; Protein Serine-Threonine Kinases; Receptors, Adrenergic; Signal Transduction; Structure-Activity Relationship; Tretinoin; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The androgen receptor (AR) represents the primary target for prostate cancer (PC) treatment even when the disease progresses toward androgen-independent (AIPC) or castration-resistant (CRPC) forms. Because small chemical changes in the structure of nonsteroidal AR ligands determine the pharmacological responses of AR, we developed a novel stereoselective synthetic strategy that allows sterically hindered C2-substituted bicalutamide analogues to be obtained. Biological and theoretical evaluations demonstrate that C2-substitution with benzyl and phenyl moieties is a new, valuable option toward improving pan-antagonist behavior. Among the synthesized compounds, (R)-16m, when compared to casodex, (R)-bicalutamide, and enzalutamide, displayed very promising in vitro activity toward five different prostate cancer cell lines, all representative of CPRC and AIPC typical mutations. Despite being less active than (R)-bicalutamide, (R)-16m also displayed marked in vivo antitumor activity on VCaP xenografts and thus it may serve as starting point for developing novel AR pan-antagonists.

Topics: Active Transport, Cell Nucleus; Androgen Receptor Antagonists; Animals; Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chlorocebus aethiops; COS Cells; Dose-Response Relationship, Drug; Humans; Male; Mice; Mice, Nude; Microscopy, Fluorescence; Models, Chemical; Models, Molecular; Molecular Structure; Mutation; Prostatic Neoplasms; Protein Conformation; Receptors, Androgen; Xenograft Model Antitumor Assays

As part of our program to explore the influence of small structural modifications of our drug candidate 3β-(hydroxy)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (galeterone, 5) on the modulation of the androgen receptor (AR), we have prepared and evaluated a series of novel C-3, C-16, and C-17 analogues. Using structure activity analysis, we established that the benzimidazole moiety at C-17 is essential and optimal and also that hydrophilic and heteroaromatic groups at C-3 enhance both antiproliferative (AP) and AR degrading (ARD) activities. The most potent antiproliferative compounds were 3β-(1H-imidazole-1-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (47), 3-((EZ)-hydroximino)-17-(1H-benzimidazol-1-yl)androsta-4,16-diene (36), and 3β-(pyridine-4-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (43), with GI50 values of 0.87, 1.91, and 2.57 μM, respectively. Compared to 5, compound 47 was 4- and 8-fold more potent with respect to AP and ARD activities, respectively. Importantly, we also discovered that our compounds, including 5, 36, 43, and 47, could degrade both full-length and truncated ARs in CWR22rv1 human prostate cancer cells. With these activities, they have potential for development as new drugs for the treatment of all forms of prostate cancer.

Topics: Androstadienes; Benzimidazoles; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Drug Design; Humans; Male; Molecular Targeted Therapy; Prostatic Neoplasms; Proteolysis; Receptors, Androgen; Steroid 17-alpha-Hydroxylase; Transcriptional Activation

Diverse cellular processes relevant to cancer progression are regulated by the acetylation status of proteins. Among such processes is chromatin remodeling via histone proteins, controlled by opposing histone deacetylase (HDAC) and histone acetyltransferase (HAT) enzymes. Histone deacetylase inhibitors (HDACi) show great promise in preclinical cancer models, but clinical trials treating solid tumors have failed to improve patient survival. This is due in part to an inability of HDACi to effectively accumulate in cancerous cells. To address this problem we designed HDACi with secondary pharmacophores to facilitate selective accumulation in malignant cells. We present the first example of HDACi compounds targeted to prostate tumors by equipping them with the additional ability to bind the androgen receptor (AR) with nonsteroidal antiandrogen moieties. Leads among these new dual-acting molecules bind to the AR and halt AR transcriptional activity at lower concentrations than clinical antiandrogens. They inhibit key isoforms of HDAC with low nanomolar potency. Fluorescent microscopy reveals varying degrees of AR nuclear localization in response to these compounds that correlates with their HDAC activity. These biological properties translate into potent anticancer activity against hormone-dependent (AR+) LNCaP and to a lesser extent against hormone-independent (AR-) DU145 prostate cancer, while having greatly reduced toxicity in noncancerous cells. This illustrates that engaging multiple biological targets with a single chemical probe can achieve both potent and cell-type-selective responses.

Topics: Androgen Antagonists; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; Drug Delivery Systems; Histone Deacetylase Inhibitors; Humans; Inhibitory Concentration 50; Male; Microscopy, Confocal; Models, Biological; Prostatic Neoplasms; Receptors, Androgen

A structure-activity relationship study was carried out on a series of thiohydantoins and their analogues 14 which led to the discovery of 92 (MDV3100) as the clinical candidate for the treatment of hormone refractory prostate cancer.

Topics: Androgen Receptor Antagonists; Androgens; Animals; Cell Line, Tumor; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Male; Orchiectomy; Prostatic Neoplasms; Receptors, Androgen; Structure-Activity Relationship; Thiohydantoins; Tumor Burden; Xenograft Model Antitumor Assays