Recent Advances in Allosteric Androgen Receptor Inhibitors for the Potential Treatment of castration-resistant Prostate Cancer

Martinez-Ariza, Guillermo; Hulme, Christopher

doi:10.4155/ppa.15.20

Cited by 12 publications

(27 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pyrvinium (69), an antihelmintic (and its hydrogenated analogue 1,2,3,4-tetrahydropyrv inium [143] ), was able to bind at the interface of the DBD dimer (inhibiting also AR splice variants lacking the LBD) and inhibit cell lines derived from both bone and prostate [144] . Although the results are promising, some doubts have been expressed about the binding site on the DBD involved in the AR inhibition by 69 [117,145] .…”

Section: Seviteronel (5mentioning

confidence: 99%

“…The AR is a validated therapeutic target for PCa and five molecules have already been approved by the FDA (cyproterone acetate 50, flutamide 51, nilutamide 52, bicalutamide 53, enzalutamide 54, Figure 13) [117] while several others are currently under preclinical/clinical development. Among papers of considerable interest on AR, we recommend the following for further reading: the report of Lu et al [118] that describes the mechanism of function of AR and its targetable domains, the review by Imamura and Sadar [6] , which focuses on ARrelated mechanisms of resistance and AR antagonist therapeutic agents undergoing clinical trials, and finally the review by Martinez-Ariza and Hulme [117] , that encompasses non-ligand-binding protein modulators of the AR.…”

Section: Androgen Receptormentioning

confidence: 99%

“…Interestingly, flufenamic acid (65, Figure 16), that has also the ability to inhibit AKR1C3, can bind BF-3 with moderate affinity (range of activity: 10-50 µmol/L) [135] . Among small molecules inhibiting this domain and described in recent reviews [117,118,125,126] , compound 66 displays excellent anti-androgen potency, antiproliferative activity against androgen-sensitive (LNCaP) and enzalutamide-resistant (MR49F) PCa cell lines, and effective inhibition of tumour growth in vivo, in both LNCaP and MR49F xenograft models [136] . The data are very promising in highlighting the therapeutic relevance of the BF-3 groove in AR function.…”

Section: Seviteronel (5mentioning

confidence: 99%

“…The potential therapeutic benefits of EPI have been demonstrated using The AR NTD contains amino acids 1-558 and is an intrinsically disordered region. Activation function-1 (AF-1) is a protein binding domain known to bind different co-regulators and its low sequence identity with other nuclear receptors renders it an appealing target for selective small molecule inhibitors [117] . The most studied AR NTD modulators are EPI compounds that have been shown to be bound covalently to AF-1 and to inhibit AR nuclear different human PCa cell lines and xenograft models in castrated male mice [140] ; a small molecule belonging to this class (EPI-506, a prodrug analogue of EPI-002 [141] ) is now under clinical evaluation in a phase I/II study in men with mCRPC that have disease progression after enzalutamide and/or abiraterone treatment (NCT02606123).…”

Section: Seviteronel (5mentioning

confidence: 99%

See 3 more Smart Citations

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

Pippione¹,

Boschi²,

Pors³

et al. 2017

JCMT

View full text Add to dashboard Cite

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.

show abstract

Section: Seviteronel (5mentioning

confidence: 99%

Section: Androgen Receptormentioning

confidence: 99%

Section: Seviteronel (5mentioning

confidence: 99%

Section: Seviteronel (5mentioning

confidence: 99%

See 2 more Smart Citations

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

Pippione¹,

Boschi²,

Pors³

et al. 2017

JCMT

View full text Add to dashboard Cite

show abstract

“…Nuclear receptors (NRs) are ligand-inducible transcription factors that are attractive drug targets due to their involvement in a multitude of physiological and pathological processes. Currently marketed drugs designed to interact with the buried ligand binding pocket (LBP) of the respective receptor are used in major indications such as oncologic, metabolic, reproductive, and immunologic diseases [1,2]. However, the success of these therapeutics is often limited by poor selectivity and resistance mechanisms that, in the worst case, reverse the antagonistic effect of a drug and promote disease [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Allosteric Binding Sites On Nuclear Receptors: Focus On Drug Efficacy and Selectivity

Fischer

Smieško

2020

IJMS

View full text Add to dashboard Cite

Nuclear receptors (NRs) are highly relevant drug targets in major indications such as oncologic, metabolic, reproductive, and immunologic diseases. However, currently, marketed drugs designed towards the orthosteric binding site of NRs often suffer from resistance mechanisms and poor selectivity. The identification of two superficial allosteric sites, activation function-2 (AF-2) and binding function-3 (BF-3), as novel drug targets sparked the development of inhibitors, while selectivity concerns due to a high conservation degree remained. To determine important pharmacophores and hydration sites among AF-2 and BF-3 of eight hormonal NRs, we systematically analyzed over 10 µs of molecular dynamics simulations including simulations in explicit water and solvent mixtures. In addition, a library of over 300 allosteric inhibitors was evaluated by molecular docking. Based on our results, we suggest the BF-3 site to offer a higher potential for drug selectivity as opposed to the AF-2 site that is more conserved among the selected receptors. Detected similarities among the AF-2 sites of various NRs urge for a broader selectivity assessment in future studies. In combination with the Supplementary Material, this work provides a foundation to improve both selectivity and potency of allosteric inhibitors in a rational manner and increase the therapeutic applicability of this promising compound class. , glucocorticoid receptor (GR), progesterone receptor (PR), and minearlocorticoid receptor (MR) share a common domain architecture as well as a similar fold regarding their ligand binding domain (LBD), the selectivity concern for allosteric NR inhibitors remains ( Figure 1B). For example, it has been reported that the AF-2 and BF-3 sites of AR and GR have a sequence identity of approximately 50% [9,28]. Further on, drug-like mimetics of coactivator peptides at the AF-2 site have the potential to disrupt protein-protein interactions for multiple NRs and, ultimately, promote off-target toxicity [16,29].While several structures with cocrystallized ligands have been determined for the AR, targeting superficial binding sites such as AF-2 and BF-3 of other receptors remains a challenge due to their comparably large size, shallowness, and high flexibility [30,31]. Knowledge regarding binding hotspots and distinct pharmacophores among structurally similar NRs is crucial for the design of effective and selective inhibitory compounds [31][32][33][34]. In this regard, cosolvent molecular dynamics (MD) simulations are a suitable computational tool to determine hotspots and assess their druggability, as well as to obtain detailed information on potentially useful pharmacophores to improve drug potency and selectivity for the site of interest. In this simulation protocol, which was inspired by crystallographic observations of small fragments binding to protein surfaces, organic solvent molecules mimicking drug fragments are added to the aqueous phase to monitor and quantify their interaction with a protein. Compared to similar methods for bi...

show abstract

Allosteric binding on nuclear receptors: Insights on screening of non-competitive endocrine-disrupting chemicals

Zhang

Chen

et al. 2022

Environment International

View full text Add to dashboard Cite

Recent Advances in Allosteric Androgen Receptor Inhibitors for the Potential Treatment of castration-resistant Prostate Cancer

Cited by 12 publications

References 58 publications

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

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

Allosteric Binding Sites On Nuclear Receptors: Focus On Drug Efficacy and Selectivity

Allosteric binding on nuclear receptors: Insights on screening of non-competitive endocrine-disrupting chemicals

Contact Info

Product

Resources

About