Drug Development for Alzheimer's neuroinflammation

Project Summary Alzheimer’s disease (AD) affects around 6 million Americans and imposes a burden of $320 billion on the US economy. Since 2003, very few medications have been approved for AD. Neuroinflammation is one of the leading mechanisms for AD pathology affecting several brain cell types and is an active target for treatment. One of the promising targets for neuroinflammation is the calcium-dependent phospholipase A2 (cPLA2) which regulates neuronal membrane excitability, polyunsaturated fatty acid metabolism, and vascular integrity. Increased activation of cPLA2 in the brain is associated with eicosanoid inflammatory lipid profiles and is observed in AD, post-stroke, Parkinson, spinal cord injury, and traumatic brain animal models. Importantly, genetic or pharmacological reduction of cPLA2 activity ameliorates disease severity across these models. Our group has demonstrated that carrying the APOE e4 (APOE4) allele, the strongest genetic risk factor for AD, activates cPLA2 in the brain. In postmortem human brain tissues, we reported eicosanoid lipid activation profiles consistent with cPLA2 activation in APOE4 AD. Despite the strong preclinical signals, no brain penetrant cPLA2 inhibitors advanced to clinical trials. Our team has established a structure-based drug discovery platform and used it to identify new lead compounds that inhibit cPLA2, confirming their potency in vitro and in cells and brain penetrance. Our current lead has an affinity, safety, and blood- brain barrier penetration consistent with drug-like properties and initial SAR suggesting high optimization potential. Moreover, we developed a brain imaging tool based on the uptake of arachidonic acid in the brain to assess the efficacy of cPLA2 inhibition in vivo. Using these platforms, we plan to establish a comprehensive SAR for our main and backup lead series and develop a screening funnel. In close collaboration with consultants and contractors, this screening funnel will then be employed to optimize the lead potency, selectivity, ADMET, and PK properties relevant for cPLA2 inhibitors, including in vivo potency and minimal toxicity profiles. This would allow for the selection of clinical candidates for the development of IND- enabling studies and preparation of IND targeting AD neuroinflammation.