AI Helps Find a Cause of Alzheimer's Disease and Identify Therapeutic Candidate

Summary

Given that PHGDH is such an important enzyme, there are past studies on its possible inhibitors. One small molecule, known as NCT-503, stood out to the researchers because it is not quite effective at impeding PHGDH’s enzymatic activity (the production of serine), which they did not want to change. NCT-503 is also able to penetrate the blood-brain-barrier, which is a desirable characteristic. They turned to AI again for three-dimensional visualization and modeling. They found that NCT-503 can access that DNA-binding substructure of PHGDH, thanks to a binding pocket. With more testing, they saw that NCT-503 does indeed inhibit PHGDH’s regulatory role. When the researchers tested NCT-503 in two mouse models of Alzheimer’s disease, they saw that it significantly alleviated Alzheimer’s progression. The treated mice demonstrated substantial improvement in their memory and anxiety tests. These tests were chosen because Alzheimer’s patients suffer from cognitive decline and increased anxiety. The researchers do acknowledge limitations of their study. One being that there is no perfect animal model for spontaneous Alzheimer’s disease. They could test NCT-503 only in the mouse models that are available, which are those with mutations in those known disease-causing genes. Still, the results are promising, according to Zhong. “Now there is a therapeutic candidate with demonstrated efficacy that has the potential of being further developed into clinical tests,” said Zhong. “There may be entirely new classes of small molecules that can potentially be leveraged for development into future therapeutics.” An advantage of small molecules is that they could even be administered orally, he added, unlike the current treatments that require infusions. The next steps will be to optimize the compound and subject it to FDA IND-enabling studies. Paper: “Transcriptional regulation by PHGDH drives amyloid pathology in Alzheimer’s disease.” Co-authors include Junchen Chen*, Fatemeh Hadi*, Xing...