Developments in Nonsteroidal Antiandrogens Targeting the Androgen Receptor

Liu, Bo; Su, Lei; Geng, Jingkun; Liu, Junjie; Zhao, Guisen

doi:10.1002/cmdc.201000259

Cited by 16 publications

(13 citation statements)

References 91 publications

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“…There are two kinds of androgen receptor antagonists, steroidal and non-steroidal chemicals 4,16 . Steroidal antiandrogens have limited clinical application due to the undesired side effects, which led to the development of nonsteroidal antiandrogens.…”

Section: Introductionmentioning

confidence: 99%

Interaction mechanism exploration of R-bicalutamide/S-1 with WT/W741L AR using molecular dynamics simulations

Liu

et al. 2015

Mol. BioSyst.

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R-Bicalutamide is a first generation antiandrogen used to treat prostate cancer, which inhibits androgen action by competitively binding to the androgen receptor (AR). However, R-bicalutamide was discovered to exhibit some agonistic properties in clinical application. According to reports, the W741L AR mutation may lead to resistance towards R-bicalutamide. But the mechanism of the R-bicalutamide switch from an antagonist to an agonist due to the mutation of AR W741L is still not so clear. Another molecule, S-1, owing to a very similar structure to R-bicalutamide, is always agonistic to both the wild type and W741L AR. The main difference between these two chemicals is that S-1 has an ether linkage while R-bicalutamide has a sulfonyl group. To study the drug-resistant mechanism caused by W741L mutation and the opposite effects arising from subtle structure differences, molecular dynamics (MD) simulations and molecular mechanics generalized Born surface area (MM-GBSA) calculations were employed to explore the interaction mechanisms between R-bicalutamide/S-1 and WT/W741L AR. The calculated binding free energies are in accordance with the reported experimental values. The obtained results indicate that M895 and W741 are vital amino acids in the antagonism of R-bicalutamide. The bulkier substitution of sulfonyl and tryptophan push aside M895, together with helix 12 (H12), to expose the ligand-binding domain resulting in the antagonistic conformation of the AR. If W741 is mutated to L741, the B-ring of these two chemicals would shift toward L741. At the same time, M895 dragging helix H12, would also move closer to L741. So H12 tends to cover the AR ligand-binding domain to a certain degree, changing the androgen receptor from an antagonistic to an agonistic conformation, which may explain the agonism of R-bicalutamide to the mutant W741L AR.

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Section: Introductionmentioning

confidence: 99%

Interaction mechanism exploration of R-bicalutamide/S-1 with WT/W741L AR using molecular dynamics simulations

Liu

et al. 2015

Mol. BioSyst.

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“…AR is located in the cytoplasm without the presence of a ligand and binds to heat‐shock proteins (HSPs). Once the LBD of AR binds DHT, the AR is dissociated from the HSPs, with a conformational change generating a hydrophobic groove, namely, AF2, on the surface and translocating it to the nucleus as a homodimer (Fig. ).…”

Section: The Structure and Signaling Pathway Of The Androgen Receptormentioning

confidence: 99%

“…The ligand‐activated AR binds to the specific androgen response elements in the DNA and interacts with coactivators through AF2. The interaction of coactivators with AF2 triggers the recruitment of RNA polymerase II and other transcriptional factors to form the transcription machinery for the target genes (TM) that are involved in the regulation of the proliferation and survival of prostate cells .…”

Section: The Structure and Signaling Pathway Of The Androgen Receptormentioning

confidence: 99%

Recent Developments in Androgen Receptor Antagonists

Ran

Xing

Liu

et al. 2015

Archiv der Pharmazie

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The androgen receptor (AR), a ligand-dependent transcription factor that regulates the expression of a series of downstream target genes after the binding of androgens, has been a target for the discovery of drugs used to treat prostate cancer. Prostate cancer always progresses to castration-resistant prostate cancer after a period of androgen deprivation therapy. Thus, developing potent androgen receptor antagonists for the therapy of castration-resistant prostate cancer possesses great significance. This review summarizes the preclinical development of androgen receptor antagonists, conventional androgen receptor antagonists that competitively bind to the ligand binding domain of the androgen receptor and coactivator antagonists of the androgen receptor, including both activation function-2 antagonists and binding function-3 antagonists. We hope that this review can help other researchers find new scaffolds and sites for the treatment of prostate cancer.

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“…The previous studies have been reported to target AR in either direct or indirect manner. For instance, these studies included AR antagonists for decreasing AR target gene expression , cytochrome inhibitors for blocking androgen synthesis , and Hsp90 inhibitors for degrading AR protein . Moreover, AR was crucial for the proliferation, survival, and metabolic processes in PCa cells .…”

Section: Introductionmentioning

confidence: 99%