Selectively targeting the dimerization interface of human androgen receptor with small-molecules to treat castration-resistant prostate cancer

Androgen receptor (AR) is closely associated with a group of hormone‐related diseases including the cancers of prostate, breast, ovary, pancreas, etc and anabolic deficiencies such as muscle atrophy and osteoporosis. Depending on the specific type and stage of the diseases, AR ligands including not only antagonists but also agonists and modulators are considered as potential therapeutics, which makes AR an extremely interesting drug target. Here, we at first review the current understandings on the structural characteristics of AR, and then address why and how AR is investigated as a drug target for the relevant diseases and summarize the representative antagonists and agonists targeting five prospective small molecule binding sites at AR, including ligand‐binding pocket, activation function‐2 site, binding function‐3 site, DNA‐binding domain, and N‐terminal domain, providing recent insights from a target and drug development view. Further comprehensive studies on AR and AR ligands would bring fruitful information and push the therapy of AR relevant diseases forward.

Section: Ar Antagonists Targeting Dbdmentioning

confidence: 98%

Section: Ar and Pcamentioning

confidence: 98%

A magic drug target: Androgen receptor

Zhou

Pang

et al. 2018

“…Another key area of extended application for the notion of AR‐DBD inhibition is to disrupt the DBD‐mediated dimerization of the AR, which is an essential step in the AR activation process . Until recently, AR dimerization (homo and hetero) was thought to exclusively occur in a head‐to‐tail fashion, facilitated by key intermolecular interactions between the D‐box regions of the two associating AR‐DBDs .…”

Section: Vpc Compounds Sklb‐c2807 and Pyrviniummentioning

confidence: 99%

“…However, new findings by Nadal et al do also indicate that the AR‐homodimerization mechanism may occur in a head‐to‐head fashion, facilitated by key intermolecular interactions between the H5 helix regions of the two associating AR‐LBD's. Using in silico methods and the former paradigm for AR dimerization, Dalal et al recently found several VPC compounds that disrupt the AR‐DBD dimerization interface. The lead compound discovered from this study, VPC‐17005, reduced the viability of LNCaP (IC 50 = 1.5 µM), MR49F (enzalutamide‐resistant; IC 50 = 1.8 µM), and 22Rv1 (enzalutamide‐resistant; IC 50 = 21 µM) cells .…”

Section: Vpc Compounds Sklb‐c2807 and Pyrviniummentioning

confidence: 99%

“…Using in silico methods and the former paradigm for AR dimerization, Dalal et al recently found several VPC compounds that disrupt the AR‐DBD dimerization interface. The lead compound discovered from this study, VPC‐17005, reduced the viability of LNCaP (IC 50 = 1.5 µM), MR49F (enzalutamide‐resistant; IC 50 = 1.8 µM), and 22Rv1 (enzalutamide‐resistant; IC 50 = 21 µM) cells . PC3 cell viability was not affected up to a concentration of 10 µM (assay limit).…”

Section: Vpc Compounds Sklb‐c2807 and Pyrviniummentioning

confidence: 99%

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Molecules targeting the androgen receptor (AR) signaling axis beyond the AR‐Ligand binding domain

Elshan¹,

Rettig

Jung³

2018

Prostate cancer (PCa) is the second most common cause of cancer-related mortality in men in the United States. The androgen receptor (AR) and the physiological pathways it regulates are central to the initiation and progression of PCa. As a member of the nuclear steroid receptor family, it is a transcription factor with three distinct functional domains (ligand-binding domain [LBD], DNA-binding domain [DBD], and transactivation domain [TAD]) in its structure. All clinically approved drugs for PCa ultimately target the AR-LBD. Clinically active drugs that target the DBD and TAD have not yet been developed due to multiple factors. Despite these limitations, the last several years have seen a rise in the discovery of molecules that could successfully target these domains. This review aims to present and comprehensively discuss such molecules that affect AR signaling through direct or indirect interactions with the AR-TAD or the DBD. The compounds discussed here include hairpin polyamides, niclosamide, marine sponge-derived small molecules (eg, EPI compounds), mahanine, VPC compounds, JN compounds, and bromodomain and extraterminal domain inhibitors. We highlight the significant in vitro and in Med Res Rev. 2019;39:910-960. wileyonlinelibrary.com/journal/med 910 | -binding domain; LRP6, low-density lipoprotein receptor-related protein 6;MAPK, mitogen-activated protein kinase; mCRPC, metastatic castration-resistant prostate cancer; mTOR, mammalian target of rapamycin; NHR, nuclear hormone receptor; PARP, poly (ADP-ribose) polymerase; PCa, prostate cancer; PI3K, phosphatidylinositol-3 kinase; PPARγ, peroxisome-proliferatoractivated receptor-γ; PR, progesterone receptor; PSA, prostate-specific antigen; PTEN, phosphatase and tensin homolog; Py, N-methylpyrrole; RNAP2, RNA polymerase II; SAR, structure-activity relationship; SPOP, speckle-type POZ protein; STAT, signal transducer and activator of transcription; TAD, transactivation domain; TMPRSS, transmembrane protease serine 2. vivo data found for each compound and the apparent limitations and/or potential for further development of these agents as PCa therapies. K E Y W O R D S androgen receptor, androgen receptor degradation, androgen receptor signaling axis, androgen receptor DNA-binding domain, androgen receptor transactivation domain, castration-resistant prostate cancer, prostate cancer 1 | INTRODUCTION 1.1 | Physiologic role and regulation of the androgen receptor The androgen receptor (AR) is a ligand-activated DNA-binding transcription factor of 110 kDa molecular weight, which facilitates the expression of androgen-dependent gene products (Figure 1). 1,2 As a member of the steroid and nuclear hormone receptor (NHR) super family, it shares many structural and functional features with other receptors such as the glucocorticoid receptor (GR), estrogen receptor (ER), mineralocorticoid receptor, progesterone receptor (PR), and the vitamin D receptor. 3,4 The nuclear steroid receptors consist of three principal domains: (1) the carboxy-terminal ligandbinding domain (...

Current and emerging approaches to noncompetitive AR inhibition

Riley

Elwood

Henry

et al. 2023

The androgen receptor (AR) has been shown to be a key determinant in the pathogenesis of castration‐resistant prostate cancer (CRPC). The current standard of care therapies targets the ligand‐binding domain of the receptor and can afford improvements to life expectancy often only in the order of months before resistance occurs. Emerging preclinical and clinical compounds that inhibit receptor activity via differentiated mechanisms of action which are orthogonal to current antiandrogens show promise for overcoming treatment resistance. In this review, we present an authoritative summary of molecules that noncompetitively target the AR. Emerging small molecule strategies for targeting alternative domains of the AR represent a promising area of research that shows significant potential for future therapies. The overall quality of lead candidates in the area of noncompetitive AR inhibition is discussed, and it identifies the key chemotypes and associated properties which are likely to be, or are currently, positioned to be first in human applications.