Novel Drug Interferes with Androgen Receptors and Blocks Prostate Cancer Growth

A novel, small molecule peptidomimetic drug called D2 interferes with the function of androgen receptors, blocking the androgen-induced proliferation of prostate cancer cells in vitro and inhibiting tumor growth in a mouse xenograft model.

A peptidomimetic is a small protein-like chain designed to mimic a peptide. These molecules typically arise either from modification of an existing peptide, or by designing similar molecules that mimic peptides, such as peptoids and beta-peptides. The altered chemical structure is designed to advantageously adjust molecular properties such as stability or biological activity. These modifications involve changes to the peptide that will not occur naturally (such as altered backbones or the incorporation of non-natural amino acids).

Investigators at the University of Texas (Dallas, USA) and colleagues at the University of Texas Southwestern Medical Center (Dallas, USA) used computer-assisted molecular modeling techniques to design a helix-mimicking small molecule that could bind selectively to a pocket on the androgen receptor associated with prostate cancer.

They reported in the May 28, 2013, online edition of the journal Nature Communications that this molecule, D2, blocked androgen-induced nuclear uptake and genomic activity of the androgen receptor. Furthermore, D2 abrogated androgen-induced proliferation of prostate cancer cells in vitro, and inhibited tumor growth in a mouse xenograft model. D2 also disrupted androgen receptor–coregulator interactions in ex vivo cultures of primary human prostate tumors. D2 was found to be stable, nontoxic, and efficiently taken up by prostate cancer cells.

"When a tumor is trying to grow, activation of this location provides what the tumor needs," said contributing author Dr. Jung-Mo Ahn, associate professor of chemistry at the University of Texas. "There are other surfaces on the androgen receptor that are free to continue working with their respective proteins and to continue functioning. We sought to block only one set of interactions that contribute to prostate cancer growth. That is why we thought our approach might lead to potent efficacy with fewer side effects."

"We have shown that our molecule binds very tightly, targeting the androgen receptor with very high affinity," said Dr. Ahn. "We also have confirmed that it inhibits androgen function in these cells, which is a promising finding for drug development. We showed that it does work through these mechanisms, and it is as effective in inhibiting the proliferation of prostate cancer cells as other compounds currently in clinical trials."


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University of Texas

University of Texas Southwestern Medical Center