University of Southern California has received a USD 1.67 million NIA U01 cooperative agreement to advance brain-penetrant small molecule inhibitors of calcium-dependent phospholipase A2 (cPLA2) toward investigational new drug (IND)-enabling studies in Alzheimer's disease (AD).
The grant supports a four-investigator team — Kai Chen, Vsevolod Katritch, Stan Gee Louie, and Hussein N. Yassine — working to optimize lead compounds identified through a structure-based drug discovery platform. The team reported that existing leads demonstrate in vitro potency, cell-based activity, and blood-brain barrier penetration consistent with drug-like properties. The project aims to refine potency, selectivity, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles across lead and backup compound series, with the goal of nominating a clinical candidate.
The cPLA2 enzyme regulates neuronal membrane phospholipid metabolism and generates eicosanoid inflammatory lipid mediators. Elevated cPLA2 activity has been associated with AD pathology, and the team said the APOE ε4 allele — the strongest common genetic risk factor for AD — activates cPLA2 in the brain. Postmortem human brain tissue analysis reportedly showed eicosanoid lipid profiles consistent with cPLA2 activation in APOE4-positive AD cases. Despite preclinical signals across AD, post-stroke, and traumatic brain injury models, no brain-penetrant cPLA2 inhibitor has entered clinical trials, the team noted.
To support in vivo efficacy assessment, the group developed a positron emission tomography (PET) imaging tool based on radiolabeled arachidonic acid uptake in the brain, intended to measure target engagement of cPLA2 inhibition without relying solely on behavioral endpoints.