Conformational dynamics of androgen receptors bound to agonists and antagonists

Gim, Hyo Jin; Park, Jiyong; Jung, Michael E.; Houk, K. N.

doi:10.1038/s41598-021-94707-2

Cited by 17 publications

(17 citation statements)

References 51 publications

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“…Conformational changes of the H11-H12 loop region have also been observed in molecular-dynamics simulations with second-generation antagonists (Balbas et al, 2013;Gim et al, 2021;Kocak & Yildiz, 2022). In the docked poses, part of enzalutamide can be positioned near the Phe877 side chain and the H11-H12 loop region, suggesting that the conformation of this region could affect ligand binding.…”

Section: A Partially Open Conformation Of Ar Lbd With Resistance Muta...mentioning

confidence: 70%

A partially open conformation of an androgen receptor ligand-binding domain with drug-resistance mutations

Doamekpor

Peng²,

Xu³

et al. 2023

Acta Cryst Sect F

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Mutations in the androgen receptor (AR) ligand-binding domain (LBD) can cause resistance to drugs used to treat prostate cancer. Commonly found mutations include L702H, W742C, H875Y, F877L and T878A, while the F877L mutation can convert second-generation antagonists such as enzalutamide and apalutamide into agonists. However, pruxelutamide, another second-generation AR antagonist, has no agonist activity with the F877L and F877L/T878A mutants and instead maintains its inhibitory activity against them. Here, it is shown that the quadruple mutation L702H/H875Y/F877L/T878A increases the soluble expression of AR LBD in complex with pruxelutamide in Escherichia coli. The crystal structure of the quadruple mutant in complex with the agonist dihydrotestosterone (DHT) reveals a partially open conformation of the AR LBD due to conformational changes in the loop connecting helices H11 and H12 (the H11–H12 loop) and Leu881. This partially open conformation creates a larger ligand-binding site for AR. Additional structural studies suggest that both the L702H and F877L mutations are important for conformational changes. This structural variability in the AR LBD could affect ligand binding as well as the resistance to antagonists.

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Section: A Partially Open Conformation Of Ar Lbd With Resistance Muta...mentioning

confidence: 70%

A partially open conformation of an androgen receptor ligand-binding domain with drug-resistance mutations

Doamekpor

Peng²,

Xu³

et al. 2023

Acta Cryst Sect F

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“…although the precise explanation for different effects between bicalutamide and enzalutamide/apalutamide in STeaP1 expression is unclear, the differences observed might be due to different affinities of these drugs to ar. in fact, it the conformational dynamics of ar with bicalutamide, enzalutamide and apalutamide was evaluated and it was shown that enzalutamide and apalutamide induce different conformational changes in ar compared with bicalutamide (58). in addition, point mutations in ar, namely F877l and T878a, are associated with resistance to enzalutamide and apalutamide, but not to bicalutamide (59)(60)(61).…”

Section: Discussionmentioning

confidence: 99%

STEAP1 regulation and its influence modulating the response of LNCaP prostate cancer cells to bicalutamide, enzalutamide and apalutamide

et al. 2023

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anti-androgen drugs are the standard pharmacological therapies for treatment of non-metastatic prostate cancer (Pca). However, the response of Pca cells may depend on the anti-androgen used and often patients become resistant to treatment. Thus, studying how the anti-androgen drugs affect oncogenes expression and action and the identification of the best strategy for combined therapies are essential to improve the efficacy of treatments. The Six Transmembrane epithelial antigen of the Prostate 1 (STeaP1) is an oncogene associated with Pca progression and aggressiveness, although its relationship with the androgen receptor signaling remains to be elucidated. The present study aimed to evaluate the effect of anti-androgens in regulating STeaP1 expression and investigate whether silencing STeaP1 can make Pca cells more sensitive to anti-androgen drugs. For this purpose, wild-type and STeaP1 knockdown lncaP cells were exposed to bicalutamide, enzalutamide and apalutamide. Bicalutamide decreased the expression of STeaP1, but enzalutamide and apalutamide increased its expression. However, decreased cell proliferation and increased apoptosis was observed in response to all drugs. overall, the cellular and molecular effects were similar between lncaP wild-type and lncaP-STeaP1 knockdown cells, except for c-myc expression levels, where a cumulative effect between anti-androgen treatment and STeaP1 knockdown was observed. The effect of STeaP1 knockdown alone or combined with anti-androgens in c-myc levels is required to be addressed in future studies.

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“…FDA approved second-generation AR antagonists Enzalutamide (also named MDV3100) is the first FDA-approved second-generation AR antagonist for the treatment of CRPC and exhibits a much higher AR-binding affinity in comparison to the first-generation AR antagonists. It competitively binds to the ligand-binding domain (LBD) of AR and inhibits androgen binding, nuclear translocation, DNA binding, and co-activator recruitment [26,27]. Enzalutamide significantly prolongs the overall survival and metastatic-free survival of CRPC patients [17,28,29], and was approved by the United States FDA for treatment of metastatic CRPC (mCRPC) and non-metastatic CRPC (nmCRPC) in 2012 and 2018, respectively.…”

Section: Development Of Second-generation Ar Antagonistsmentioning

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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Conformational dynamics of androgen receptors bound to agonists and antagonists

Cited by 17 publications

References 51 publications

A partially open conformation of an androgen receptor ligand-binding domain with drug-resistance mutations

A partially open conformation of an androgen receptor ligand-binding domain with drug-resistance mutations

STEAP1 regulation and its influence modulating the response of LNCaP prostate cancer cells to bicalutamide, enzalutamide and apalutamide

Second generation androgen receptor antagonists and challenges in prostate cancer treatment

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