化放療嚴重口腔黏膜炎(severe oral mucositis): pyridine-2,6- dicarboxyaldehyde, manganese(II) chloride +tetramine合成抗氧化物 clinical phase III前進

Poised for phase 3, Galera's GC4419 wards off radiation side effects by Amirah Al Idrus | Aug 20, 2018 For many head and neck cancer patients who receive radiation therapy, side effects, such as oral mucositis, are a fact of life. This inflammatory condition cannot be prevented and can only be treated once it develops, but a synthetic enzyme from Galera Therapeutics could change that. In data to be presented Monday at a meeting of the American Chemical Society, the enzyme mimetic, dubbed GC4419, appears to stave off severe oral mucositis (SOM), a condition in which the epithelial cells lining the gastrointestinal tract break down. SOM opens the mucus membranes to ulceration and infection, which in turn can lead to further side effects. Because they cannot eat, patients with SOM may need feeding tubes as well as narcotic analgesics to ease their pain. The condition can also be dose-limiting; that is, subsequent chemotherapy may have to be given in reduced doses or delayed altogether. Radiation triggers a rise in superoxide radical levels, which are thought to lead to oral mucositis and other side effects. In the study, the researchers showed that GC4419 converts superoxide to molecular oxygen and hydrogen peroxide. The enzyme could deliver a one-two punch against cancer—in addition to getting rid of superoxide, it increases levels of hydrogen peroxide, which kills cancer cells. "The synthetic enzyme we designed and made mimics the function of the naturally occurring superoxide dismutase, an enzyme that converts superoxide to molecular oxygen and hydrogen peroxide," Riley said. "Hydrogen peroxide is very toxic to cancer cells but not to normal cells. Thus, we create two opportunities to improve radiation therapy: reducing toxicity for normal cells while increasing the toxicity to the cancerous ones."

GC4419 is just one of several dismutase mimetics in Galera's pipeline. "We had to figure out which isomer would work best and be the most 'druggable,'" Riley said. "Our current synthesis involves using a template to make the 15-membered macrocylic ring complex in a single GMP [Good Manufacturing Practice] step. It uses pyridine-2,6- dicarboxyaldehyde, manganese(II) chloride and a linear tetramine synthesized from S,S-1,2 diaminocyclohexane. It is an elegantly simple 'one-pot' synthesis that yields the desired molecule with more than 99.5 percent chemical purity." GC4419 has completed phase 1 and 2 trials and is poised to enter phase 3 this year. If approved, it could be used to ward off SOM and its side effects not just in patients with head and neck cancers, but in those with other types of cancer. For example, it may be useful in pancreatic cancer, which is often diagnosed at late stages and is hard to treat because of the pancreas' location deep within the abdomen."[In pancreatic cancer] you might want to use high-dose radiation for locally advanced disease, but the pancreas is too close to other organs that cannot handle the side effects of radiation," Riley said. "We are currently studying GC4419's anti-tumor effect in a Phase 1/2 clinical trial in pancreatic cancer at MD Anderson Cancer Center."