Galeterone

INTRODUCTION: Tumor immunotherapy targeting PD-L1 has emerged as one of the powerful tools for tumor therapy. Numerous studies indicate that tumor-targeted drugs critically have an influence on the interaction between the immune system and tumors by changing the expression of PD-L1, which is beneficial for immunotherapy. Our study provided novel evidence for improving the drug regimen in tumor targeted therapy and immunotherapy. METHODS: 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)...

Galeterone, 3β-(hydroxy)-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (Gal, 1) and VNPP433-3β, 3β-(1H-imidazole-1-yl-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (2) are potent molecular glue degrader modulators of AR/AR-V7 and Mnk1/2-eIF4E signaling pathways, and are promising Phase 3 and Phase 1 drug candidates, respectively. Because appropriate salts can be utilized to create new chemical entities with enhanced aqueous solubility, in vivo pharmacokinetics, and enhanced in vitro and in vivo efficacies, the monohydrochloride salt of Gal (3) and the mono- and di-hydrochlorides salts of compound 2, compounds 4 and 5, respectively, were synthesized...

Galeterone, a novel prostate cancer candidate treatment, was discontinued after a Phase III clinical trial due to lack of efficacy. Galeterone is weakly basic and exhibits low solubility in biorelevant media (i.e., ~ 2 µg/mL in fasted simulated intestinal fluid). It was formulated as a 50-50 (w/w) galeterone-hypromellose acetate succinate spray-dried dispersion to increase its bioavailability. Despite this increase, the bioavailability of this formulation may have been insufficient and contributed to its clinical failure...

Targeted protein degradation is a fast-evolving therapeutic strategy to target even the traditionally undruggable target proteins. Contrary to the traditional small-molecule inhibitors of enzyme or receptor antagonists that bind the active site pockets in the target protein, molecular glue degraders facilitate interaction of target proteins with E3 ubiquitin ligases by stabilizing the ternary complex and induce physical proximity, thereby triggering ubiquitination and subsequent proteasomal degradation. AR plays a key role in all stages of prostate cancer...

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). Compound 2 is currently in development as potential new therapeutic for prostate and pancreatic cancers. The preliminary toxicity study reveals that the compound 2 was better tolerated by the normal male CD-1 mice than the male Nude mice. The maximum tolerated dose (MTD) in the Nude mice was estimated to be between 25 < 50 mg/kg...

Estrogens play a pivotal role in the development of estrogen-dependent breast cancer and other hormone-dependent disorders. A common strategy to overcome the pathological effects of estrogens is the use of aromatase inhibitors (AIs), which bind to the enzyme and prevent the union with the natural substrate, decreasing the amount of estrogens produced. Several AIs have been developed, including inhibitors with a steroidal backbone and a nitrogen heterocycle in their structure. Encouraged by the notable results presented by current and clinical steroidal drugs, herein we present the synthesis of a steroidal spiro morpholinone derivative as a plausible aromatase inhibitor...

Prostate cancer (PCa) relies in part on AR-signaling for disease development and progression. Earlier, we developed drug candidate galeterone, which advanced through phase 2-clinical trials in treating castration-resistant PCa (CRPC). Subsequently, we designed, synthesized, and evaluated next-generation galeterone-analogs including VNPP433-3β which is potently efficacious against pre-clinical models of PCa. This study describes the mechanism of action of VNPP433-3β that promotes degradation of full-length AR (fAR) and its splice variant AR-V7 besides depleting MNK1/2 in in vitro and in vivo CRPC models that stably overexpresses fAR...

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 67-b with the dual functions of AR antagonism and degradation. In vitro , 67-b exhibited excellent antiproliferative activity and potent AR degradation activity in different PCa cells (LNCaP and 22RV1), as well as outstanding antagonistic activity against wild-type and mutant (W741L, T877A, and F876L) ARs...

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). Here, we describe a large multi-gram (92 g) scale synthesis of compound 2 starting from the commercially available dehydroepiandrosterone-3-acetate (DHEA, 6) via Galeterone (Gal, 1), in 8 steps with a 26% overall yield and 99.5% purity. The overall yield for the synthesis of Gal from DHEA improved from previously reported 47% to 59%...

Cancer stem cells (CSCs) virtually present in all tumors albeit in small numbers are primarily responsible for driving cancer progression, metastasis, drug resistance, and recurrence. Prostate cancer (PCa) is the second most frequent cancer in men worldwide, and castration resistant prostate cancer (CRPC) remains a major challenge despite the tremendous advancements in medicine. Currently, none of the available treatment options are effective in treating CRPC. We earlier reported that VNPP433-3β, the lead next-generation galeterone analog is effective in treating preclinical in vivo models of CRPC...

Morusflavone, a flavonoid from Morus alba L., was evaluated for its interactive ability and stability with CYP17A1, in comparison with abiraterone, which is a Food and Drug Administration (FDA)-approved CYP17A1 inhibitor. CYP17A1 inhibition is an important therapeutic target for prostate cancer. The CHAMM36 force field was used to perform molecular dynamics (MD) simulations in this study. The results show that Morusflavone has significant interactive ability and stability for CYP17A1, in comparison with abiraterone...

Benzimidazole is nitrogen containing fused heterocycle which has been extensively explored in medicinal chemistry. Benzimidizole nucleus has been found to possess various biological activities such as anticancer, antimicrobial, anti-inflammatory, antiviral, antitubercular and antidiabetic. 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...

This mini-review focuses on the investigation of novel nitrogen-containing steroid derivatives that are potentially applicable for prostate cancer treatment. It covers the literature of the last decade, highlighting the structure of new steroid compounds that exhibit significant activity in prostate cancer cells and possess 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...

Aberrant activation of eIF4E signalling pathway is common in breast cancer and holds potential therapeutic options. In our work, galeterone as a chemical compound under clinical trials for the treatment of prostate cancer, was identified to be effective in targeting breast cancer cells via suppressing MNK-eIF4E and β-catenin. In despite of varying IC50, galeterone at nanomolar concentrations significantly decreased viability, proliferation and migration of a panel of breast cancer cell lines regardless of clinical subtypes and genetic mutations, and to a higher extent than in normal breast cells...

We have investigated interactions of galeterone and its pharmacologically active metabolite - 3-keto-Δ4-galeterone (D4G) - with one of the key enzymes of corticosteroid biosynthesis - steroid 21-monooxygenase (CYP21A2). It was shown by absorption spectroscopy that both compounds induce type I spectral changes of CYP21A2. Spectral dissociation constants (Ks ) of complexes of CYP21A2 with galeterone or D4G were calculated as 3.1 ± 0.7 μM and 4.6 ± 0.4 μM respectively. It was predicted by molecular docking that both ligands similarly bind to the active site of CYP21A2...

Abiraterone acetate (AA) is a prodrug of abiraterone (Abi), a CYP17A1 inhibitor used to treat patients with advanced prostate cancer (PCa). Abi is a selective steroidal inhibitor that blocks the biosynthesis of androgens. It undergoes extensive biotransformation by steroid pathways leading to the formation of pharmacologically active Δ4-abiraterone (D4A) and 5α-abiraterone (5α-Abi). This study aimed to characterize the glucuronidation pathway of Abi and its two active metabolites. We show that Abi, its metabolites and another steroidal inhibitor galeterone (Gal), undergo secondary metabolism to form glucuronides (G) in human liver microsomes with minor formation by intestine and kidney microsomal preparations...

Seven new oxazoline, benzoxazole and benzimidazole derivatives were synthesized from 3β-acetoxyandrosta-5,16-dien-17-carboxylic, 3β-acetoxyandrost-5-en-17β-carboxylic and 3β-acetoxypregn-5-en-21-oic acids. Docking to active site of human 17α-hydroxylase/17,20-lyase revealed that all oxazolines, as well as benzoxazoles and benzimidazoles comprising Δ16 could form stable complexes with enzyme, in which steroid moiety is positioned similarly to that of abiraterone and galeterone, and nitrogen atom coordinates heme iron, while 16,17-saturated benzoxazoles and benzimidazoles could only bind in a position where heterocycle is located nearly parallel to heme plane...

These studies compared the efficacies of our clinical agent galeterone (Gal) and the FDA-approved prostate cancer drug, enzalutamide (ENZ) with two lead next generation galeterone analogs (NGGAs), VNPP414 and VNPP433-3β, using prostate cancer (PC) in vitro and in vivo models. Antitumor activities of orally administered agents were also assessed in CWR22Rv1 tumor-bearing mice. We demonstrated that Gal and NGGAs degraded AR/AR-V7 and Mnk1/2; blocked cell cycle progression and proliferation of human PC cells; induced apoptosis; inhibited cell migration, invasion, and putative stem cell markers; and reversed the expression of epithelial-to-mesenchymal transition (EMT)...

BACKGROUND: Detection of androgen receptor (AR) splice variant-7 (AR-V7) messenger RNA (mRNA) in circulating tumor cells (CTCs) is associated with a suboptimal response to abiraterone and enzalutamide in metastatic castration-resistant prostate cancer (mCRPC). Galeterone inhibits CYP17 and AR, and induces AR protein degradation. We hypothesized that galeterone would be clinically superior to enzalutamide in AR-V7-positive (AR-V7+) mCRPC. OBJECTIVE: To screen and characterize AR-V7+ mCRPC, and evaluate galeterone compared with enzalutamide...

The incorporation of the heterocycles into the steroid nucleus has been recognized as a useful strategy to develop new steroidal agents for disease treatment. Representative examples are abiraterone and galeterone, which are presently used in clinic for the treatment of advanced prostate cancers. Herein we have developed the first Al2 O3 /KF-promoted pfitzinger reactions for the synthesis of new steroidal quinolines. These new steroidal quinolines showed moderate to good antiproliferative activity against several human lung cancer cells...