Researchers from Cincinnati Children’s Hospital Medical Center found a new compound with therapeutic potential to block a protein called FOXM1, which is responsible for pro-inflammatory and hyper-mucous activity in asthma and other chronic airway disorders.
The finding was reported in the study “The FOXM1 inhibitor RCM-1 suppresses goblet cell metaplasia and prevents IL-13 and STAT6 signaling in allergen-exposed mice,” recently published in the journal Science Signaling.
Current standard care for patients with severe asthma and other debilitating lung diseases is focused in the reduction of lung and airway inflammation. However, in many cases, this strategy is not very effective and it does not stop disease progression.
Targeting directly genes that are on the core of the disease, causing inflammation and promoting the expansion of mucous-producing goblet cells, may pave the path for new and more efficient therapeutic drugs.
A research team led by Vladimir Kalinichenko identified, from a library of about 50,000 small molecules, a compound called RCM-1 that was able to inhibit FOXM1 and its downstream pro-inflammatory activity.
FOXM1 is a protein from the family of transcription factors, and is responsible for the control of several genes, including some involved in inflammation and activation of mucus-producing cells. Because it is found in the nucleus of cells and is hard to reach, FOXM1 is considered an “undruggable” target. However, if efficiently targeted, it can modulate the entire cellular response.
“Traditional targets for drugs are receptors on cell surfaces, which are easy to reach. Transcription factors are inside cell nuclei and difficult to reach,” said Kalinichenko in a press release.
The researchers found that the RCM-1 drug could reduce the expression of FOXM1 in both human airway cells and mouse models of asthma. The drug also prevented FOXM1 from entering the nucleus, inhibiting is normal activity. Treatment with RCM-1 decreased the airway hyper-responsiveness to allergen, reduced lung inflammation, and improved lung function in mice.
“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 mucous-generating goblet cells in our tests”, Kalinichenko said.
These results need to be further tested in more sophisticated pre-clinical animal models of respiratory diseases, addressing the safety, toxicity and efficiency of the new drug before moving forward to clinical trials. In addition, the research team plans to develop further studies to improve RCM-1 delivery in a therapeutic and clinical setting.
The researchers have applied for a patent on RCM-1, working through the Cincinnati Children’s Center for Technology Commercialization.
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