UCSD-776890

UCSD-776890 is a small molecule gamma-secretase modulator (GSM) developed through a collaboration between the University of California San Diego and Massachusetts General Hospital. As a pyridazine-derived compound, it allosterically modulates the gamma-secretase enzyme rather than inhibiting it, which shifts the cleavage of amyloid precursor protein (APP) to reduce the production of neurotoxic amyloid-beta peptides Aβ40 and Aβ42 while concomitantly increasing the levels of shorter, non-aggregating peptides like Aβ38 and Aβ37. This mechanism is intended to avoid the side effects associated with gamma-secretase inhibitors (GSIs), such as interference with Notch signaling. The drug is being developed for the treatment and prevention of Alzheimer's disease, including early-onset familial Alzheimer's disease (EOFAD) and Alzheimer's disease in Down syndrome (AD-DS). As of 2022, it had completed preclinical development and was entering Phase I clinical evaluation in the MODIFY trial.