galeterone (TOK-001) / Eledon - LARVOL DELTA

Drug-like molecules targeting androgen receptor's allosteric binding sites selected by augmented AI and high-throughput screening as antitumor agents against prostate cancer. (PubMed, Biomed Pharmacother) - "These compounds surpassed treatments like enzalutamide and galeterone in inhibiting colony and sphere formation, indicating new therapeutic potential...Furthermore, immunofluorescence assay on PC3 cells, demonstrated that compound 77 inhibits the nuclear translocation of GR following dexamethasone treatment, which is used to induce GR nuclear translocation. Furthermore, these findings revealed that compound 77 significantly reduces the transcription of GR and its downstream gene FKBP5, a classical GR target gene. These results substantiate our hypothesis that compound 77, particularly engages in off-target interactions, thereby potentially disrupting cancer growth."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • FKBP5

Thermal proteome profiling and proteome analysis using high-definition mass spectrometry demonstrate modulation of cholesterol biosynthesis by next-generation galeterone analog VNPP433-3β in castration-resistant prostate cancer. (PubMed, Mol Oncol) - "The inhibition of CHOL biosynthesis by VNPP433-3β reinforces its multifaceted effects in PCa across all stages, highlighting its potential as a single-agent therapy. Achieving reduced CHOL levels aligns with better treatment outcomes, further substantiating VNPP433-3β's therapeutic potential."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

Galeterone monotherapy in advanced pancreatic ductal adenocarcinoma: Results from a phase two trial. (ASCO-GI 2025) - P2 | "Galeterone showed no clinical activity, but with a favorable safety profile, as a single-agent in heavily pre-treated patients with advanced PDAC. Activation of the Mnk-eIF4E axis mediates chemoresistance in PDAC and galeterone may prove more efficacious with gemcitabine. This combination arm is currently open to enrollment."

Metastases • Monotherapy • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • EIF4E

Abiraterone and Galeterone, Powerful Tools Against Prostate Cancer: Present and Perspective. (PubMed, Pharmaceutics) - "Besides prostate cancer treatment, abiraterone showed indications for possible clinical application in the treatment of breast, ovarian, lung, kidney, salivary gland, and adrenocortical cancer, congenital adrenal hyperplasia, Cushing's syndrome, and COVID-19, while galeterone is investigated for its use against prostate, pancreatic, and breast cancer. Herein, we report a review comprising methods of synthesis, possible clinical applications, and mechanisms of action, as well as structures and bioactivities of derivatives of these two important steroids."

Journal • Review • Adrenal Cortex Carcinoma • Breast Cancer • Castration-Resistant Prostate Cancer • Congenital Adrenal Hyperplasia • Cushing’s Disease • Endocrine Disorders • Genito-urinary Cancer • Infectious Disease • Novel Coronavirus Disease • Oncology • Pancreatic Cancer • Prostate Cancer • Solid Tumor

Sterol-like drugs potentiate statin-triggered prostate cancer cell death by inhibiting SREBP2 nuclear translocation (EACR 2024) - "Molecular modeling techniques were utilized to assess the structural similarity of identified compounds to 25-hydroxy-cholesterol (25HC) and predict their binding to a known protein-binding site of 25HC.Results and Discussions Two compounds, Galeterone (GAL) and Quinestrol, emerged as validated hits from the drug screen. These compounds share a cholesterol-related tetracyclic structure reminiscent of the FDA-approved CRPC drug Abiraterone (ABI)...Importantly, sensitivity to these compounds was independent of androgen status. Furthermore, the combination of Fluva and GAL significantly impeded CRPC tumor xenograft growth, indicating their potential as a potent therapeutic strategy against CRPC progression.Conclusion By identifying cholesterol-mimetic drugs that inhibit SREBP2 activation upon statin treatment, we provide a potent "one-two punch" against CRPC progression and pave the way for innovative therapeutic strategies to combat additional diseases whose..."

Castration-Resistant Prostate Cancer • Dyslipidemia • Genito-urinary Cancer • Metabolic Disorders • Oncology • Prostate Cancer • Solid Tumor

Sterol-like drugs potentiate statin-triggered prostate cancer cell death by inhibiting SREBP2 nuclear translocation. (PubMed, Biomed Pharmacother) - "Two of the validated hits, Galeterone (GAL) and Quinestrol, share the cholesterol-related tetracyclic structure, which is also evident in the FDA-approved CRPC drug Abiraterone (ABI). Sensitivity was independent of androgen status and the Fluva-GAL combination significantly impeded CRPC tumor xenograft growth. By identifying cholesterol-mimetic drugs that inhibit SREBP2 activation upon statin treatment, we provide a potent "one-two punch" against CRPC progression and pave the way for innovative therapeutic strategies to combat additional diseases whose etiology is associated with SREBP2 dysregulation."

Journal • Castration-Resistant Prostate Cancer • Dyslipidemia • Genito-urinary Cancer • Metabolic Disorders • Oncology • Prostate Cancer • Solid Tumor

AURKA inhibitor-induced PD-L1 upregulation impairs antitumor immune responses. (PubMed, Front Immunol) - "The expression of PD-L1 on SKBR3, MDA-MB-231, MCF7, 4T1, MC38 and B16 cells was evaluated by flow cytometry after treatment with six preclinical targeted drugs (ARN-509, AZD3514, Galeterone, Neratinib, MLN8237 and LGK974). When treated with MLN8237 in combination with anti-PD-L1 antibody, the volumes of tumor were significantly reduced and accompanied by increasing the infiltration of CD3+ and CD8+ T cells in colorectal cancer xenograft tumor model. Our data demonstrated that MLN8237 improved the effect of immunology-related therapy on tumor cells by interacting with anti-PD-L1 antibody, which contributed to producing creative sparks for exploring the possible solutions to overcoming drug resistance to tumor targeted therapy."

IO biomarker • Journal • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD8 • STAT3

Salinization Dramatically Enhance the Anti-Prostate Cancer Efficacies of AR/AR-V7 and Mnk1/2 Molecular Glue Degraders, Galeterone and VNPP433-3β Which Outperform Docetaxel and Enzalutamide in CRPC CWR22Rv1 Xenograft Mouse Model. (PubMed, Bioorg Chem) - "Finally, and most importantly, oral administration of the parent compounds (1 and 2) and their corresponding salts (3, 4 and 5) caused dose-dependent potent inhibition/regression of aggressive and difficult-to-treat CWR22Rv1 tumor xenografts growth, with no apparent host toxicities and were highly more efficacious than the blockbuster FDA-approved prostate cancer drugs, Enzalutamide (Xtandi) and Docetaxel (Taxotere). Thus, the HCl salts of Gal (3) and VNPP433-3β (4 and 5) are excellent orally bioavailable candidates for clinical development."

Journal • Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • AR • EIF4E

Can the Oral Bioavailability of the Discontinued Prostate Cancer Drug Galeterone Be Improved by Processing Method? KinetiSol® Outperforms Spray Drying in a Head-to-head Comparison. (PubMed, AAPS PharmSciTech) - "When compared to a spray-dried dispersion with an equivalent drug load, the KinetiSol amorphous solid dispersions formulations exhibited ~ 2 × exposure in an in vivo rat study. Acid-base surface energy analysis showed that the equivalent composition of the KinetiSol amorphous solid dispersion formulation better protected the weakly basic galeterone from premature dissolution in acidic media and thereby reduced precipitation, inhibited recrystallization, and extended the extent of supersaturation during transit into neutral intestinal media."

Head-to-Head • Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Targeted Degradation of Androgen Receptor by VNPP433-3β in Castration-Resistant Prostate Cancer Cells Implicates Interaction with E3 Ligase MDM2 Resulting in Ubiquitin-Proteasomal Degradation. (PubMed, Cancers (Basel)) - "It is activated by the binding of androgenic hormones and transcriptionally regulates multiple genes including the ones that regulate cell cycle. Using HiBiT CRISPR cell line, biochemical methods, and RNA sequencing, we report the potential role of VNPP433-3β, the next generation galeterone analog as molecular glue that brings together AR, the key driver of prostate cancer and MDM2, an E3 ubiquitin ligase leading to ubiquitination and subsequent degradation of f-AR and AR-V7 in prostate cancer cells."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • AR

Murine Toxicology and Pharmacokinetics of Lead Next Generation Galeterone Analog, VNPP433-3β. (PubMed, Steroids) - "is clearly not zero. Clearly, these toxicology and pharmacokinetics parameters pave the way for understanding the anticancer pharmacological actions and provide a meaningful basis for further preclinical development and eventual clinical development."

Journal • PK/PD data • Preclinical • Gastrointestinal Cancer • Gastrointestinal Disorder • Genito-urinary Cancer • Hepatology • Oncology • Oral Cancer • Pancreatic Cancer • Prostate Cancer • Solid Tumor

Synthesis, antiproliferative evaluation and in silico studies of a novel steroidal spiro morpholinone. (PubMed, Steroids) - "Furthermore, both compounds showed, in almost all cases, better GI values than the steroidal anticancer drugs abiraterone and galeterone. The results showed interactions with the iron heme (derivative 3) and important residues of the steroidal binding-site (Met374) for the inhibition of human aromatase. A correlation was found between in vitro assays and the score obtained from the molecular docking study."

Journal • Breast Cancer • Oncology • Solid Tumor

Clinical factors associated with AR-V7 detection in ARMOR3-SV, a randomized trial of galeterone (Gal) vs enzalutamide (Enz) in men with AR-V7+ metastatic castration-resistant prostate cancer (mCRPC). (ASCO 2017) - P3; "...Background: Presence of the AR-V7 splice variant may predict resistance to Enz and abiraterone in men with mCRPC...AR-V7 detection was associated with higher PSA levels ( > vs 20 vs 11-20 vs 6-10 vs 0-5; P median; P < 0.01), higher ECOG (≥1 vs 0; P = 0.02), prior antiandrogen use (yes vs no; P < 0.01) and prior docetaxel use (yes vs no; P < 0.01)... In treatment-naïve mCRPC patients, AR-V7 detection is more common in men with higher disease burden and portends a poor prognosis. Novel study designs and alternative treatment approaches are urgently needed for AR-V7+ mCRPC patients."

Clinical • Biosimilar • Prostate Cancer

Novel AR/AR-V7 and Mnk1/2 Degrader, VNPP433-3β: Molecular Mechanisms of Action and Efficacy in AR-Overexpressing Castration Resistant Prostate Cancer In Vitro and In Vivo Models. (PubMed, Cells) - "Earlier, we developed drug candidate galeterone, which advanced through phase 2-clinical trials in treating castration-resistant PCa (CRPC)...Finally, RNA-seq demonstrates modulation of multiple pathways that synergistically contribute to PCa inhibition. Therefore, VNPP433-3β exerts its antitumor effect by imposing 1) transcriptional regulation of AR and AR-responsive oncogenes 2) translational regulation by disrupting mRNA-5'cap-dependent translation initiation, 3) reducing AR half-life through enhanced proteasomal degradation in vitro and AR-overexpressing tumor xenografts in vivo."

Journal • Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • AR • CAST • EIF4E • EIF4EBP1 • EIF4G1 • HSP90AA1

Design, Synthesis, and Biological Evaluation of Androgen Receptor Degrading and Antagonizing Bifunctional Steroidal Analogs for the Treatment of Advanced Prostate Cancer. (PubMed, J Med Chem) - "Herein, systemic structural modifications on the C-3, C-6, and C-17 positions of galeterone led to the discovery of 67-b with the dual functions of AR antagonism and degradation. In vivo, 67-b effectively inhibited the growth of hormone-sensitive organs in the Hershberger assay and exhibited tumor regression in the enzalutamide-resistant (c4-2b-ENZ) xenograft model. These results confirmed 67-b to be a promising AR degrader and antagonist for the treatment of mCRPC patients."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

Large-scale synthesis of galeterone and lead next generation galeterone analog VNPP433-3β. (PubMed, Steroids) - "VNPP433-3β (compound 2, (3β-(1H-imidazole-1-yl)-17-(1H-benzimidazole-1-yl)-androsta-5,16-diene), a multitarget anticancer agent has emerged as our lead next generation galeterone analogs (NGGA). The structure of the target product (2, VNPP433-3β) was established by NMR spectroscopy, mass spectrometry and elemental analysis. Gal and VNPP433-3β exhibit more potent antiproliferative activities against CWR22Rv1 human prostate cancer cells compared to clinical drugs, Abiraterone and Enzalutamide."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Transcriptome profiling reveals that VNPP433-3β, the lead next-generation galeterone analog inhibits prostate cancer stem cells by downregulating epithelial-mesenchymal transition and stem cell markers. (PubMed, Mol Carcinog) - "VNPP433-3β inhibits CSCs in PCa, presumably by degrading the androgen receptor (AR) thereby decreasing the AR-mediated transcription of several stem cell markers including BMI1 and KLF4. Transcriptome analyses by RNA-seq, Ingenuity Pathway Analysis, and Gene Set Enrichment Analysis demonstrate that VNPP433-3β inhibits transcription of several genes and functional pathways critical to the prostate CSCs thereby inhibiting CSCs in PCa besides targeting the bulk of the tumor."

Cancer stem cells • Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • BMI1 • KLF4

ARMOR2: A 2 Part, Phase 2 Trial of Galeterone in the Treatment of Castration Resistant Prostate Cancer (clinicaltrials.gov) - P2; N=126; Completed; Sponsor: Novus Therapeutics, Inc; Active, not recruiting ➔ Completed

Trial completion • Biosimilar • Prostate Cancer

[VIRTUAL] Mechanistic insights on the effects of the lead next generation galeterone analog, VNPP433-3β in castration resistant prostate cancer (AACR-NCI-EORTC 2021) - No abstract available

Late-breaking abstract • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Morusflavone, a New Therapeutic Candidate for Prostate Cancer by CYP17A1 Inhibition: Exhibited by Molecular Docking and Dynamics Simulation. (PubMed, Plants (Basel)) - "Since there are only limited therapeutic agents available, such as abiraterone, galeterone, and seviteronel, which are being developed for prostate cancer, information on any potent natural anticancer compounds, such as vinca alkaloids, for prostate cancer treatment is limited. The results of this study show that CYP17A1 inhibition by Morusflavone could be an important therapeutic target for prostate cancer. Further preclinical and clinical evaluations of the lead compound Morusflavone are required to evaluate whether it can serve as a potential inhibitor of CYP17A1, which will be a new hope for prostate cancer treatment."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CYP17A1

Recent advancements on Benzimidazole: A versatile scaffold in medicinal chemistry. (PubMed, Mini Rev Med Chem) - "A number of benzimidazoles such as bendamustine, pantoprazole have been approved for the treatment of various illnesses whereas galeterone and GSK461364 are in clinical trials. The present review article gives an overview about the different biological activities exhibited by the benzimidazole derivatives as well as different methods used for the synthesis of benzimidazole derivatives for the past ten years."

Journal • Oncology

Novel nitrogen containing steroid derivatives for prostate cancer treatment. (PubMed, Curr Med Chem) - "It covers last decade of literature with highlights on the structure of new steroid compounds exhibiting significant activity in prostate cancer cells and possessing pharmacological potency. New derivatives of known anti-prostate cancer agents: abiraterone and galeterone, new derivatives of androstane and pregnane modified with nitrogen containing heterocycles, and some related steroid derived compounds are discussed in the review."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Galeterone sensitizes breast cancer to chemotherapy via targeting MNK/eIF4E and β-catenin. (PubMed, Cancer Chemother Pharmacol) - "Rescue studies demonstrated that both MNK/eIF4E and β-catenin were responsible for anti-breast cancer activity of galeterone. Our study provides pre-clinical evidence to initialize clinical trials for breast cancer using galeterone in combination with chemotherapy."

Journal • Breast Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • EIF4E

Androgen Receptor Modulation Optimized for Response-Splice Variant: A Phase 3, Randomized Trial of Galeterone Versus Enzalutamide in Androgen Receptor Splice Variant-7-expressing Metastatic Castration-resistant Prostate Cancer. (PubMed, Eur Urol) - "The prevalence of CTC mRNA AR-V7 in first-line mCRPC was 8% (95% CI 6-10%). AR-V7+ was associated with the characteristics of aggressive and advanced disease. These men had rapid disease progression. Development of galeterone will not be pursued."

Biomarker • Clinical • Journal • P3 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • CTCs

Interactions of galeterone and its 3-keto-Δ4 metabolite (D4G) with one of the key enzymes of corticosteroid biosynthesis - steroid 21-monooxygenase (CYP21A2). (PubMed, Fundam Clin Pharmacol) - "We have revealed using reconstituted monooxygenase system that galeterone is a competitive inhibitor of CYP21A2 with the inhibition constant (K ) value of 12 ± 3 μM, while D4G at the concentrations of 10 μM and 25 μM does not inhibit the enzyme. Summarizing, based on the in vitro analyses we detected inhibition of CYP21A2 by galeterone and lack of the influence of D4G on this enzyme."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CYP1A2