Research discovers drug target for prostate cancer
potential new target for treating prostate cancer, a disease driven
in part by abnormal testosterone activity, which affects one in six
American men.
The discovery brings hope to sufferers of the most common cancer among men. Knowing the detailed shape greatly boosts the likelihood of developing a drug to block this binding and turn off androgen receptor activity.
Prostate cancer is a disease mainly driven by abnormal testosterone activity and is the most common cancer among men. The target is part of the androgen receptor, a protein essential for testosterone to function in human cells.
The androgen receptor and testosterone (5-alpha dihydrotestosterone) each drive prostate cancer at different stages of the disease. A common prostate cancer treatment uses drugs that compete with testosterone, blocking its ability to bind with the androgen receptor and reducing the hormone's effect.
However, the cancer tends to become resistant to these drugs and new research provides a novel strategy to block activation of both the androgen receptor and testosterone.
The scientists, from the University of California (UCSF), determined the shape of the binding pocket on the androgen receptor by exposing it to billions of randomly chosen peptides, and selecting for those that bind best. They then imaged the peptides that bind best using a technology called X-ray diffraction that shows every atom of the peptide and the receptor, and how they interact.
Robert Fletterick, senior author on the paper said: "Drugs that block testosterone binding are not effective in the long term against prostate cancer. The shape of the site specifies the design for a new class of drugs. Simple versions of the 'ultimate' drug will be tested in cancer cells this year."
Fletterick added that with an aggressive search for the right chemicals, candidate drugs might be tested in human patients within three years.
Meanwhile the University of California has filed for a patent revealing the nature of the coactivator site on the androgen receptor.
The researchers are now testing the ability of small different molecules to bind to the androgen receptor binding site. They hope to demonstrate the potential of developing a drug that will bind more strongly, thereby shutting down androgen receptor activity.
"Knowing the molecular shape of the target speeds development of a new drug about ten-fold," Fletterick said. "This helps assure the drug will work as expected."
"In addition, chemists can use the information to synthesize new molecules with the required drug traits."
However Fletterick commented that it would remain uncertain as to whether researchers can identify a small molecule drug candidate that binds to the coactivator more strongly than the coactivators themselves do.
Cancer researchers do not know which coactivators bind with the androgen receptor when cancer strikes. However the research may lead to selective drugs that permit 'good' activators to bind while blocking those that promote cancer progression. This possibility is the focus of new research by several UCSF labs.
