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Targeting androgen receptor for prostate cancer therapy: From small molecules to PROTACs

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Summary: Multiple splice variants of AR have been reported in CRPC cases, with AR-V7 being extensively characterized and explored as a potential biomarker through clinical trials. A potent and selective AR-V7 degrader has been developed using computational algorithms and rational SAR optimization, showing promise for pharmacological evaluation and further lead compound development.

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Youquan Xie et al.

Summary: This article reviews the potential of selective androgen receptor modulators (SARMs) as a treatment for osteoporosis and summarizes the structure and structure-activity relationships (SAR) of SARMs. Promising SARMs molecules have been discovered and are undergoing clinical trial evaluation. However, finding SARMs with high activity and reduced side effects remains a challenge.

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Effects of MTX-23, a Novel PROTAC of Androgen Receptor Splice Variant-7 and Androgen Receptor, on CRPC Resistant to Second-Line Antiandrogen Therapy

Geun Taek Lee et al.

Summary: MTX-23 is a novel PROTAC small molecule that can simultaneously degrade AR-V7 and AR-FL, inhibiting proliferation of CRPC cells resistant to antiandrogen therapy and significantly reducing proliferation and inducing apoptosis in sensitive cells.

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Targeting transcriptional regulation of SARS-CoV-2 entry factors ACE2 and TMPRSS2

Yuanyuan Qiao et al.

Summary: Research has shown that androgens regulate the expression of ACE2, TMPRSS2, and AR in lung epithelial cells, affecting the risk of COVID-19 infection in males over 70 years old. The use of AR or BET antagonists can inhibit SARS-CoV-2 infection, providing support for further investigation into transcriptional inhibition for the treatment or prevention of COVID-19.

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Michael L. Mohler et al.

Summary: Traditional endocrine therapy for prostate cancer focuses on androgen receptor signaling suppression, but in castration-resistant prostate cancer patients, AR axis remains active. Recent evidence suggests targeting noncanonical direct binding sites on AR may provide a new approach to inhibit the AR axis.

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Development of Novel Inhibitors Targeting the D-Box of the DNA Binding Domain of Androgen Receptor

Mariia Radaeva et al.

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Linrong Chen et al.

Summary: A031 is a highly effective androgen receptor degrader that induces the degradation of AR protein in VCaP cell lines in a time-dependent manner with an IC50 value of less than 0.25 mM. It is 5 times less toxic than EZLA and shows significant inhibitory effects on tumor growth in zebrafish transplanted with human prostate cancer (VCaP), providing a promising candidate for developing novel drugs for prostate cancer.

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Xiaoyu Zhang et al.

Summary: Ligand-induced protein degradation through electrophilic PROTACs has been shown to degrade proteins in human cells by engaging specific cysteines in the poorly characterized E3 ligase substrate adaptor DCAF11. These findings suggest DCAF11 as a potential E3 ligase for ligand-induced protein degradation via electrophilic PROTACs, providing new insights for the development of targeted protein degradation compounds.

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Chemical Degradation of Androgen Receptor (AR) Using Bicalutamide Analog-Thalidomide PROTACs

Ga Yeong Kim et al.

Summary: A series of PROTACs consisting of bicalutamide analogs and thalidomides were designed, synthesized, and evaluated for their ability to degrade androgen receptor in cancer cells. Among them, compound 13b showed targeted degradation of AR in AR-positive cancer cells, suggesting its potential as a chemical probe for AR-dependent cancer cells and a therapeutic candidate for prostate cancers.

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Asher Mullard

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Keith T. Schmidt et al.

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Jian-Jia Liang et al.

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Weiguo Xiang et al.

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Yali He et al.

Summary: A series of propanamide derivatives were designed, synthesized, and characterized as selective androgen receptor degraders (SARDs) and pan-antagonists, showing efficacy against enzalutamide-resistant prostate cancers.

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Strategies toward Discovery of Potent and Orally Bioavailable Proteolysis Targeting Chimera Degraders of Androgen Receptor for the Treatment of Prostate Cancer

Xin Han et al.

Summary: This study outlines strategies for discovering highly potent PROTAC degraders of androgen receptor (AR) with excellent oral pharmacokinetics, successfully identifying compound ARD-2128 as the most effective in inhibiting tumor growth in mice with good oral bioavailability.

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Fuqiang Ban et al.

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Structure-Activity Relationships for the Marine Natural Product Sintokamides: Androgen Receptor N-Terminus Antagonists of Interest for Treatment of Metastatic Castration-Resistant Prostate Cancer

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