mdv-3100 and Prostatic-Neoplasms--Castration-Resistant

The androgen receptor (AR) plays a key role in the maintenance of muscle and bone and the support of male sexual-related functions, as well as in the progression of prostate cancer. Accordingly, AR-targeted therapies have been developed for the treatment of related human diseases and conditions. AR agonists are an important class of drugs in the treatment of bone loss and muscle atrophy. AR antagonists have also been developed for the treatment of prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC). Additionally, selective AR degraders (SARDs) have been reported. More recently, heterobifunctional degrader molecules of AR have been developed, and four such compounds are now in clinical development for the treatment of human prostate cancer. This review attempts to summarize the different types of compounds designed to target AR and the current frontiers of research on this important therapeutic target.

Topics: Androgen Antagonists; Androgen Receptor Antagonists; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen

Metastatic castration-resistant prostate cancer (mCRPC) with high mortality has seriously threatened men's health. Bifunctional agents simultaneously degrade and antagonize androgen receptor (AR), display robust AR signaling pathway blockade, and show the therapeutic prospect for mCRPC. Herein, systemic structural modifications on the C-3, C-6, and C-17 positions of galeterone led to the discovery of

Topics: Androgen Receptor Antagonists; Cell Line, Tumor; Cell Proliferation; Hormones; Humans; Male; Nitriles; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen

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

We report herein the discovery of exceptionally potent and orally bioavailable PROTAC AR degraders with ARD-2585 being the most promising compound. ARD-2585 achieves DC

Topics: Adaptor Proteins, Signal Transducing; Androgen Receptor Antagonists; Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Design; Humans; Male; Mice, SCID; Molecular Structure; Phthalimides; Piperidones; Prostatic Neoplasms, Castration-Resistant; Proteolysis; Receptors, Androgen; Structure-Activity Relationship; Xenograft Model Antitumor Assays

Prostate cancer (PCa) patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate cancer (CRPC). Targeting the androgen receptor (AR) Binding Function-3 (BF3) site offers a promising option to treat CRPC. However, BF3 inhibitors have been limited by poor potency or inadequate metabolic stability. Through extensive medicinal chemistry, molecular modeling, and biochemistry, we identified 2-(5,6,7-trifluoro-1

Topics: Administration, Oral; Androgen Antagonists; Antineoplastic Agents; Biological Availability; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Development; Drug Screening Assays, Antitumor; Humans; Male; Models, Molecular; Molecular Structure; Prostatic Neoplasms, Castration-Resistant; Quinolines; Receptors, Androgen; Structure-Activity Relationship

Aldo-keto reductase (AKR) 1C3 catalyzes the synthesis of active androgens that promote the progression of prostate cancer. AKR1C3 also contributes to androgen-independent cell proliferation and survival through the metabolism of prostaglandins and reactive aldehydes. Because of its elevation in castration-resistant prostate cancer (CRPC) tissues, AKR1C3 is a promising therapeutic target for CRPC. In this study, we found a novel potent AKR1C3 inhibitor,

Topics: Aldo-Keto Reductase Family 1 Member C3; Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Drug Design; Enzyme Inhibitors; G1 Phase Cell Cycle Checkpoints; Humans; Male; Mice, Inbred BALB C; PC-3 Cells; Prostatic Neoplasms, Castration-Resistant; 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

Prostate cancer (PC) is the second most common malignancy in men worldwide. Among current therapies, two antiandrogens, Abiraterone Acetate and Enzalutamide (Enza) have become the standard of care for patients with metastatic castration-resistant prostate cancer (mCRPC). Here, we designed and synthesized a new series of nonsteroidal compounds deriving from the hybridization of Abiraterone (Abi) and Enzalutamide, among which compound 4a featuring the diphenylamine scaffold was identified as a potent and cell selective androgen receptor (AR) antagonist. In cell proliferation assays, compound 4a exhibited better antiproliferative activities than Enzalutamide against AR-overexpressing VCaP cells and 22Rv1 cells bearing H874Y-mutated AR. In addition, 4a suppressed the activity of AR-F876L mutant that confers resistance to Enzalutamide and efficiently blocked R1881-induced PSA and FKBP5 gene expression. In competitive binding assay, compound 4a displayed higher binding affinity to AR than Enzalutamide. These results suggest compound 4a as a potential candidate to treat Enza-resistant CRPC.

Topics: Androgen Receptor Antagonists; Antineoplastic Agents; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Humans; Male; Models, Molecular; Molecular Structure; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Structure-Activity Relationship; Tumor Cells, Cultured

We report the design, optimization, and biological evaluation of nuclear receptor RORγ inverse agonists as therapeutic agents for prostate cancer treatment. The most potent compound 27 (designated as XY101) exhibited cellular activity with an IC

Topics: Acetanilides; Animals; Antineoplastic Agents; Binding Sites; Cell Proliferation; Drug Design; Drug Inverse Agonism; Gene Expression; Male; Mice; Microsomes, Liver; Molecular Docking Simulation; Molecular Structure; Nuclear Receptor Subfamily 1, Group F, Member 3; Prostatic Neoplasms, Castration-Resistant; Protein Binding; Rats; Structure-Activity Relationship; Sulfonamides; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; E1A-Associated p300 Protein; Humans; Indoles; Male; Molecular Structure; Peptide Fragments; Prostatic Neoplasms, Castration-Resistant; Sialoglycoproteins; Structure-Activity Relationship; Tumor Cells, Cultured

The bromodomain and extra-terminal (BET) family proteins have gained increasing interest as drug targets for treatment of castration-resistant prostate cancer (CRPC). Here, we describe the design, optimization, and evaluation of benzo[ d]isoxazole-containing compounds as potent BET bromodomain inhibitors. Cocrystal structures of the representative inhibitors in complex with BRD4(1) provided solid structural basis for compound optimization. The two most potent compounds, 6i (Y06036) and 7m (Y06137), bound to the BRD4(1) bromodomain with K

Topics: Animals; Antineoplastic Agents; Cell Cycle Proteins; Cell Division; Drug Design; Drug Discovery; Gene Expression Regulation, Neoplastic; Humans; Isoxazoles; Male; Mice; Models, Molecular; Nuclear Proteins; Prostatic Neoplasms, Castration-Resistant; Proteins; Structure-Activity Relationship; Substrate Specificity; Transcription Factors; Tumor Stem Cell Assay; Xenograft Model Antitumor Assays

The bromodomain and extra-terminal proteins (BET) have emerged as promising therapeutic targets for the treatment of castration-resistant prostate cancer (CRPC). We report the design, synthesis and evaluation of a new series of benzoxazinone-containing 3,5-dimethylisoxazole derivatives as selective BET inhibitors. One of the new compounds, (R)-12 (Y02234), binds to BRD4(1) with a K

Topics: Animals; Antineoplastic Agents; Benzoxazines; Cell Movement; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Isoxazoles; Male; Molecular Structure; Prostatic Neoplasms, Castration-Resistant; Proteins; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Tumor Cells, Cultured

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.

Topics: Allosteric Site; Amides; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Indoles; Male; Models, Molecular; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Small Molecule Libraries; Structure-Activity Relationship