Development of novel androgen receptor antagonists based on the structure of darolutamide

Xu, Qian; Zhang, Zixiong; Huang, Chen-Chao; Bao, Qiqi; Zhang, Rongyu; Wu, Meng; Xiao, Xiaohui; Han, Xiaoli; Li, Xiaoyü; Zhou, Jinming

doi:10.1016/j.bioorg.2022.105829

Cited by 2 publications

(3 citation statements)

References 32 publications

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“…To investigate the binding mode of GA32 with AR or GR, the molecular docking was performed using the DOCK module in the molecular modeling package molecular operating environment (MOE). To date, the crystal structure of AR-LBD in the antagonistic form has not been resolved, and the antagonistic model of AR-LBD (PDB-ID: 1Z95) was constructed as previously described through molecular modeling 4MDD).…”

Section: Resultsmentioning

confidence: 99%

“…To date, the crystal structure of AR-LBD in the antagonistic form has not been resolved, and the antagonistic model of AR-LBD (PDB-ID: 1Z95) was constructed as previously described through molecular modeling. 25 GA32 was docked into the HBP site of the AR-LBD model as well as that of the GR-LBD structure (PDB-ID: 4MDD). Molecular dynamics simulations were further performed to explore the more accurate interaction model between GA32 and AR or GR (Figure S3).…”

Section: ■ Introductionmentioning

confidence: 99%

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Design and Synthesis of Dual-Target Inhibitors Targeting Androgen Receptors and Glucocorticoid Receptors to Overcome Antiandrogen Resistance in Castration-Resistant Prostate Cancer

Li,

Han,

Yan

et al. 2024

J. Med. Chem.

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Androgen receptor (AR) antagonists play important roles in the treatment of castration-resistant prostate cancer (CRPC). The glucocorticoid receptor (GR) upregulation leads to drug resistance for clinically used antiandrogens. Therefore, blocking AR/GR signaling simultaneously has become an efficient strategy to overcome the drug resistance of CRPC. Our previous work indicated that Z19 could inhibit the activity of both AR and GR. Herein, we optimized the structure of Z19 and identified GA32 as a potent AR/GR dual inhibitor. GA32 efficiently reduced the mRNA and protein levels of AR/GR downstream genes. GA32 efficiently inhibited the proliferation of enzalutamide resistance CRPC both in vitro and in vivo. GA32 could directly bind to AR and GR, and the predicted binding modes for GA32 with AR/GR suggested that GA32 binds to the AR or GR hormone binding pocket. This work provides a potential lead compound with dual AR/GR inhibitory activity to conquer the drug resistance of CRPC.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Design and Synthesis of Dual-Target Inhibitors Targeting Androgen Receptors and Glucocorticoid Receptors to Overcome Antiandrogen Resistance in Castration-Resistant Prostate Cancer

Li,

Han,

Yan

et al. 2024

J. Med. Chem.

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“…It is not yet clear whether combination therapy of low dose of TRC-253 with other androgen inhibitors such as abiraterone can lower its toxicity and improve the anti-tumor effect. A more recent study has developed several AR antagonists based on the structure of darolutamide, from which "compound 28t" has been found to show superior efficacy against two resistant mutants (AR-F876L and AR-T877A) relative to darolutamide [53]. Further clinical trials are needed to assess its safety, pharmacokinetics, and efficiency.…”

Section: Emerging Ar Antagonists In Clinical Trialsmentioning

confidence: 99%

Second generation androgen receptor antagonists and challenges in prostate cancer treatment

et al. 2022

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Prostate cancer is a hormone-dependent malignancy, whose onset and progression are closely related to the activity of the androgen receptor (AR) signaling pathway. Due to this critical role of AR signaling in driving prostate cancer, therapy targeting the AR pathway has been the mainstay strategy for metastatic prostate cancer treatment. The utility of these agents has expanded with the emergence of second-generation AR antagonists, which began with the approval of enzalutamide in 2012 by the United States Food and Drug Administration (FDA). Together with apalutamide and darolutamide, which were approved in 2018 and 2019, respectively, these agents have improved the survival of patients with prostate cancer, with applications for both androgen-dependent and castration-resistant disease. While patients receiving these drugs receive a benefit in the form of prolonged survival, they are not cured and ultimately progress to lethal neuroendocrine prostate cancer (NEPC). Here we summarize the current state of AR antagonist development and highlight the emerging challenges of their clinical application and the potential resistance mechanisms, which might be addressed by combination therapies or the development of novel AR-targeted therapies.

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Development of novel androgen receptor antagonists based on the structure of darolutamide

Cited by 2 publications

References 32 publications

Design and Synthesis of Dual-Target Inhibitors Targeting Androgen Receptors and Glucocorticoid Receptors to Overcome Antiandrogen Resistance in Castration-Resistant Prostate Cancer

Design and Synthesis of Dual-Target Inhibitors Targeting Androgen Receptors and Glucocorticoid Receptors to Overcome Antiandrogen Resistance in Castration-Resistant Prostate Cancer

Second generation androgen receptor antagonists and challenges in prostate cancer treatment

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