AR splice variant 7

AminoTriComplex was associated with consistent biomarker modulation and occasional exceptional responses; these hypothesis-generating observations warrant validation in larger controlled trials.

91 exhibited favorable pharmacokinetic properties (F = 41%) and significant tumor growth inhibition in CRPC orthotopic models, achieving 66% TGI. This study characterized a distinct subpocket of CDK9 and validated 91 as a promising candidate, paving the way for developing CDK9-targeted therapies to overcome AR dependency in CRPC.

In vivo, ARTADIs outperformed enzalutamide against prostate cancer xenografts in the presence of androgens, underscoring the therapeutic potential of targeting alternative AR domains. These findings support the feasibility - but also highlight the complexity - of developing drugs against an intrinsically disordered TAD impacted by multivalent binding interactions that may not occur in a stepwise fashion.

Maintained B7-H3 expression in various PC settings supports its viability as a target. Associations with AR-related molecular factors, surface antigens, and investigative targets for cell therapy or antibody-drug conjugates (ADC) suggest potential dual-targeting strategies.

Notably, WCF-598 also exhibited a secondary activity by degrading androgen receptor splice variant 7 (AR-V7), a clinically relevant driver of therapy resistance in CRPC. These results establish WCF-598 as a specific chemical probe for investigating the function of RXRγ in CRPC and potentially other RXRγ-related diseases.

The novel arylpiperazine derivative NAF19 exerts multi-targeted antitumor effects by concurrently inhibiting AR/AR-Vs signaling pathways and activating apoptotic cascades, thereby potently suppressing the migratory, invasive, and proliferative capacities of prostate cancer cells.

This study clarifies the clinical relevance of cytoplasmic AR-V7 in circulating tumor cells from men with metastatic castration-resistant prostate cancer. While nuclear-localized AR-V7 predicts extremely poor response, PFS, and overall survival with AR pathway inhibitors, cytoplasmic AR-V7 expands the definition of AR-V7-positive status and identifies patients with equally poor PFS and intermediate response and overall survival outcomes. Assessing both nuclear and cytoplasmic AR-V7 fractions may thus improve risk stratification heterogeneity and could better guide poor-risk ARPI treatment decisions by avoiding ineffective ARPI treatment, helping personalize therapy, and improving outcomes in men with mCRPC.

In conclusion, AR-mutated mCRPC frequently exhibits low AR-V7 expression, arguably explaining the enhanced sensitivity to ARPIs observed in these cancers. Consequently, AR mutation status may serve as a biomarker to predict response to AR-directed therapies.

TRA2B expression correlated with AR-V7 transcript in CRPC and attenuation of TRA2-mediated splicing diminished PC cell growth. Exploiting TRA2B function may therefore provide new therapeutic opportunities in advanced disease.

While no significant difference was observed in BCR, the trend suggests potential implications for disease monitoring. Further studies with standardized detection methods are needed to clarify AR-V7's role in risk stratification and treatment decisions.

Mechanistically, IF-induced metabolic stress engages AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), and sirtuin pathways, alters lipid and mitochondrial metabolism, and transiently increases reactive oxygen species (ROS), creating vulnerabilities in prostate tumor cells. Translational evidence suggests potential benefits of integrating IF with standard therapy, but effects may depend on fasting regimen, caloric intake, macronutrient composition, and patient metabolic context, including risk of lean mass loss. This review highlights the metabolic crosstalk between IF and AR signaling and emphasizes the need for future clinical studies incorporating biomarker-guided approaches and body composition monitoring to fully exploit this intersection for improved therapeutic outcomes in prostate cancer.

When appended to the BET bromodomain inhibitor JQ1, this optimized handle yielded a potent and selective BRD4 degrader whose activity was dependent on RNF126. Importantly, transplantation of this handle onto a previously non-inhibitory ligand targeting the androgen receptor (AR) and its truncation variant, AR-V7, enabled selective degradation of both AR and AR-V7 in androgen-independent prostate cancer cells, thereby robustly inhibiting AR transcriptional activity beyond the established AR antagonist enzalutamide. Collectively, these findings demonstrate an optimized RNF126-based covalent handle for the rational development of molecular glue degraders against transcriptional regulators, including undruggable variants such as AR-V7.