PHGDH-deg

PHGDH-deg is a novel, brain-penetrant molecular glue degrader that targets phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in the serine biosynthesis pathway. Developed by researchers at the University of California, San Francisco (UCSF), PHGDH-deg is designed to exploit the metabolic dependency of H3K27M-mutated diffuse midline gliomas (DMGs) on de novo serine synthesis. By inducing the proteasomal degradation of PHGDH, the compound effectively shuts down serine production from glucose, leading to a cascade of metabolic failures including the depletion of nucleotides, sphingolipids, and glutathione. This results in significant oxidative stress and cell death via ferroptosis. Preclinical evidence demonstrates that PHGDH-deg successfully crosses the blood-brain barrier and induces tumor regression in intracranial DMG xenograft models, suggesting high potential for clinical translation in treating these lethal pediatric brain tumors.