Small-molecule androgen receptor downregulators as an approach to treatment of advanced prostate cancer

Bradbury, Robert H.; Hales, Neil J.; Rabow, Alfred A.; Walker, Graeme E.; Acton, David; Andrews, David M.; Ballard, Peter; Brooks, Nigel; Colclough, Nicola; Girdwood, Alan; Hancox, Urs J.; Jones, Owen D.; Jude, David A.; Loddick, Sarah A.; Mortlock, Andrew A.

doi:10.1016/j.bmcl.2011.06.122

Cited by 44 publications

(28 citation statements)

References 20 publications

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“…Thus, a strategy involving the removal of AR protein should have use within different stages of current prostate cancer treatment practice, such an approach having the ability to inhibit both androgendependent and -independent AR signaling. To obtain such an inhibitor, we established a cellular assay that was designed to identify compounds that modulated the level of AR in the nucleus of LNCaP prostate cancer cells in androgen-free conditions (30). This work yielded AZD3514, a small-molecule inhibitor of AR signaling that is also able to downregulate AR.…”

Section: Discussionmentioning

confidence: 99%

“…6C) was obtained by the published procedure (30). For in vivo studies, ARD1 was prepared in a suspension of 1% polysorbate 80.…”

Section: Ard1mentioning

confidence: 99%

“…Further details of instrument set up are included in Supplementary Methods for reference. Both the TSQ Vantage and 4000 QTRAP were operated in SRM mode to selectively measure the following AR peptides: GAFQNLFQSVR (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) and LLDSVQPIAR (862-871). The unlabeled, "heavy" labeled ( 13 C 6 , 15 N 4 R, þ10 Da), and "medium" labeled ( 13 C 6 , þ6 Da) forms of both peptides were measured in parallel.…”

Section: Relative Peptide Quantification By Srmmentioning

confidence: 99%

“…AZD3514 was identified using a cellular assay designed to detect compounds with the ability to cause AR downregulation [described previously for a related series of compounds (30)]. Details relating to the identification of AZD3514 compound have been recently described (29) The ability of AZD3514 to inhibit AR function was assessed in LNCaP and LAPC4 prostate cancer cells that express the T877A ligand-binding domain mutation of AR and wild-type AR, respectively (33,34).…”

Section: Azd3514 Inhibits Ar Signaling In Vitro and In Vivomentioning

confidence: 99%

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AZD3514: A Small Molecule That Modulates Androgen Receptor Signaling and Function In Vitro and In Vivo

Loddick

Ross

Thomason

et al. 2013

Molecular Cancer Therapeutics

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Continued androgen receptor (AR) expression and signaling is a key driver in castration-resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed, and therefore remains a target for the treatment of progressive disease. Here, we describe the biological characterization of AZD3514, an orally bioavailable drug that inhibits androgen-dependent and -independent AR signaling. AZD3514 modulates AR signaling through two distinct mechanisms, an inhibition of ligand-driven nuclear translocation of AR and a downregulation of receptor levels, both of which were observed in vitro and in vivo. AZD3514 inhibited testosterone-driven seminal vesicle development in juvenile male rats and the growth of androgen-dependent Dunning R3327H prostate tumors in adult rats. Furthermore, this class of compound showed antitumor activity in the HID28 mouse model of CRPC in vivo. AZD3514 is currently in phase I clinical evaluation.

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Section: Discussionmentioning

confidence: 99%

“…6C) was obtained by the published procedure (30). For in vivo studies, ARD1 was prepared in a suspension of 1% polysorbate 80.…”

Section: Ard1mentioning

confidence: 99%

Section: Relative Peptide Quantification By Srmmentioning

confidence: 99%

Section: Azd3514 Inhibits Ar Signaling In Vitro and In Vivomentioning

confidence: 99%

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AZD3514: A Small Molecule That Modulates Androgen Receptor Signaling and Function In Vitro and In Vivo

Loddick

Ross

Thomason

et al. 2013

Molecular Cancer Therapeutics

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“…Bradbury et al [154] showed that molecules containing hydrophobic regions linked to small-molecule AR ligands induce AR degradation, reduce expression of AR target genes and inhibit proliferation in androgen-dependent PCa cell lines. By appending the alkylfluoryl chain of fulvestrant onto DHT, a selective SARD compound was discovered.…”

Section: Seviteronel (5mentioning

confidence: 99%

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

Pippione¹,

Boschi²,

Pors³

et al. 2017

JCMT

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Androgens play an important role in prostate cancer (PCa) development and progression. Although androgen deprivation therapy remains the front-line treatment for advanced prostate cancer, patients eventually relapse with the lethal form of the disease. The prostate tumor microenvironment is characterised by elevated tissue androgens that are capable of activating the androgen receptor (AR). Inhibiting the steroidogenic enzymes that play vital roles in the biosynthesis of testosterone (T) and dihydrotestosterone (DHT) seems to be an attractive strategy for PCa therapies. Emerging data suggest a role for the enzymes mediating pre-receptor control of T and DHT biosynthesis by alternative pathways in controlling intratumoral androgen levels, and thereby influencing PCa progression. This supports the idea for the development of multi-targeting strategies, involving both dual and multiple inhibitors of androgen-metabolising enzymes that are able to affect androgen synthesis and signalling at different points in the biosynthesis. In this review, we will focus on CYP17A1, AKR1C3, HSD17B3 and SRD5A, as these enzymes play essential roles in all the three androgenic pathways. We will review also the AR as an additional target for the design of bifunctional drugs. Targeting intracrine androgens and AKR1C3 have potential to overcome enzalutamide and abiraterone resistance and improve survival of advanced prostate cancer patients.

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Stability of Steroid Hormone Receptors

Gale‐Day

Gestwicki

2022

Protein Homeostasis in Drug Discovery

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Small-molecule androgen receptor downregulators as an approach to treatment of advanced prostate cancer

Cited by 44 publications

References 20 publications

AZD3514: A Small Molecule That Modulates Androgen Receptor Signaling and Function In Vitro and In Vivo

AZD3514: A Small Molecule That Modulates Androgen Receptor Signaling and Function In Vitro and In Vivo

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

Stability of Steroid Hormone Receptors

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