Structure-based Virtual Screening and Identification of a Novel Androgen Receptor Antagonist

Song, Chunli; Yang, Suhui; Park, Eunsook; Cho, Suk Hee; Gong, Eun-Yeung; Khadka, Daulat Bikram; Cho, Won‐Jea; Lee, Keesook

doi:10.1074/jbc.m112.379107

Cited by 43 publications

(32 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AR mRNA transcript in LNCaP and 22Rv1 cells has been reported previously [22][23][24]. PC3 cells had been reported previously as having no or negligible AR expression [23,25], and DU145 cells as AR-negative [26]. These results are in accord with our own results.…”

Section: Discussionsupporting

confidence: 93%

Expression profiles and functional associations of endogenous androgen receptor and caveolin-1 in prostate cancer cell lines

et al. 2013

View full text Add to dashboard Cite

show abstract

Section: Discussionsupporting

confidence: 93%

Expression profiles and functional associations of endogenous androgen receptor and caveolin-1 in prostate cancer cell lines

et al. 2013

View full text Add to dashboard Cite

show abstract

“…PPC-1 cell lines were obtained from Prof. Keesook Lee (Chonnam National University, Korea) and cultured in Dulbecco's modified eagle media (DMEM; Welgene; ref. 22). Media were supplemented with 10% (v/v) heat inactivated FBS (Welgene), 100 units/mL of penicillin, and 100 mg/mL of streptomycin (Welgene).…”

Section: Cell Linesmentioning

confidence: 99%

Enhancement of the Tumor Penetration of Monoclonal Antibody by Fusion of a Neuropilin-Targeting Peptide Improves the Antitumor Efficacy

Shin

Sung

Kim

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

The limited localization and penetration of monoclonal antibodies (mAb) into solid tumors restricts their antitumor efficacy. Here, we describe a solid tumor-targeting antibody with enhanced tumor penetration activity. We designed a 22-residue peptide (A22p), which was extracted from the C-terminal basic region of semaphorin 3A (Sema3A) but modified to have higher affinity with neuropilin receptors (NRP), and genetically fused it to the C-terminus of Fc of human immunoglobulin G1 via a 15-residue (G 4 S) 3 linker, generating FcA22p, for the bivalent binding to NRPs. In contrast to Fc or the monovalent A22p peptide alone, Fc-A22p homed to tumor vessels and induced vascular permeability through VE-cadherin downregulation and penetrated tumor tissues by interacting with NRPs in mice bearing human tumor xenografts. We extended the Fc-A22p platform by generating mAb-A22p antibodies of two clinically approved solid tumor-targeting mAbs, the anti-EGF receptor mAb cetuximab (erbitux), and the anti-Her2 mAb trastuzumab (herceptin). The mAb-A22p antibodies retained the intrinsic antigen binding, natural Fc-like biophysical properties, and productivity in mammalian cell cultures, comparable with those of the parent mAbs. In mouse xenograft tumor models, the mAb-A22p antibodies more efficiently homed to tumor vessels and spread into the extravascular tumor parenchyma, which significantly enhanced antitumor efficacy compared with the parent mAbs. Our results suggest that mAb-A22p is a superior format for solid tumor-targeting antibodies due to its enhanced tumor tissue penetration and greater antitumor efficacy compared with conventional mAbs.

show abstract

“…Recent advances in the area of rational and computer-aided drug design have resulted in the development of a number of other candidate anti-androgens targeting the androgen-binding site, including compounds, such as 6-(3,4-dihydro-1 H -isoquinolin-2-yl)- N -(6-methylpyridin-2-yl)nicotinamide (DIMN) [12], its derivatives, termed 7AU and 7BB [115], and 8-(propan-2-yl)-5,6-dihydro-4 H -pyrazino[3,2,1-jk]carbazole (MEL-3) [116], all showing promising in vitro and in vivo activities and currently undergoing various stages of pre-clinical development.…”

Section: Targeting the Lbdmentioning

confidence: 99%

Targeting Alternative Sites on the Androgen Receptor to Treat Castration-Resistant Prostate Cancer

Lallous

Dalal

Cherkasov

et al. 2013

IJMS

View full text Add to dashboard Cite

Recurrent, metastatic prostate cancer continues to be a leading cause of cancer-death in men. The androgen receptor (AR) is a modular, ligand-inducible transcription factor that regulates the expression of genes that can drive the progression of this disease, and as a consequence, this receptor is a key therapeutic target for controlling prostate cancer. The current drugs designed to directly inhibit the AR are called anti-androgens, and all act by competing with androgens for binding to the androgen/ligand binding site. Unfortunately, with the inevitable progression of the cancer to castration resistance, many of these drugs become ineffective. However, there are numerous other regulatory sites on this protein that have not been exploited therapeutically. The regulation of AR activity involves a cascade of complex interactions with numerous chaperones, co-factors and co-regulatory proteins, leading ultimately to direct binding of AR dimers to specific DNA androgen response elements within the promoter and enhancers of androgen-regulated genes. As part of the family of nuclear receptors, the AR is organized into modular structural and functional domains with specialized roles in facilitating their inter-molecular interactions. These regions of the AR present attractive, yet largely unexploited, drug target sites for reducing or eliminating androgen signaling in prostate cancers. The design of small molecule inhibitors targeting these specific AR domains is only now being realized and is the culmination of decades of work, including crystallographic and biochemistry approaches to map the shape and accessibility of the AR surfaces and cavities. Here, we review the structure of the AR protein and describe recent advancements in inhibiting its activity with small molecules specifically designed to target areas distinct from the receptor’s androgen binding site. It is anticipated that these new classes of anti-AR drugs will provide an additional arsenal to treat castration-resistant prostate cancer.

show abstract

Structure-based Virtual Screening and Identification of a Novel Androgen Receptor Antagonist

Cited by 43 publications

References 96 publications

Expression profiles and functional associations of endogenous androgen receptor and caveolin-1 in prostate cancer cell lines

Expression profiles and functional associations of endogenous androgen receptor and caveolin-1 in prostate cancer cell lines

Enhancement of the Tumor Penetration of Monoclonal Antibody by Fusion of a Neuropilin-Targeting Peptide Improves the Antitumor Efficacy

Targeting Alternative Sites on the Androgen Receptor to Treat Castration-Resistant Prostate Cancer

Contact Info

Product

Resources

About