RCM-1 Blocks Transcription Factor Behind Excessive Mucus Production in Cystic Fibrosis, Asthma
Published Apr. 18, 2017
Science Signaling
For many years, transcription factors—the tiny proteins that switch genes on or off in cells—were considered unreachable targets for drug treatments.
Now, however, a research team led by experts at Cincinnati Children’s reports discovering a small-molecule compound that blocks a transcription factor known to trigger excessive mucus production in people with asthma, cystic fibrosis, and other chronic lung conditions.
The compound, dubbed RCM-1, inhibits the transcription factor FOXM1 and a downstream chain of pro-inflammatory processes. Ultimately, the treatment prevents overproduction of mucus-generating goblet cells in the lungs.
Vladimir Kalinichenko, MD, PhD, led a team that included colleagues at Cincinnati Children’s, Shandong University in China, and National Tsing Hua University in Taiwan.
“Traditional targets for drugs are receptors on cell surfaces, which are easy to reach. Transcription factors are inside cell nuclei and difficult to reach,” Kalinichenko says. “RCM-1 keeps FOXM1 from entering the cell nucleus by activating cell machinery called proteasomes that degrade the transcription factor. This was very efficient at reducing lung inflammation and production of mucus-generating goblet cells in our tests.”
In mice, RCM-1 prevented airway hyper-reactivity and inflammation and improved lung function by inhibiting IL-13 signaling, which triggers goblet cell metaplasia. This suggests that RCM-1 could become a potentially important treatment for asthma and other chronic pulmonary disorders.
The researchers have obtained a patent on the compound. Still, before any new medication might reach patients, more research will be needed to address dosage, toxicity, and optimal delivery methods.
The latest findings reflect ongoing studies of FOXM1 at Cincinnati Children’s. Kalinichenko’s team identified RCM-1 during a computer-supported screening of 50,000 compounds stored at the University of Cincinnati Genome Research Center.
