SUMMARY This R35 leadership application is relevant to Milestone 6D of the goals/milestones of the NIH Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) Summits—“Initiate drug discovery efforts to develop novel therapeutic agents.” Our overriding goal in this application is to support the infrastructure the PI is assembling for AD/ADRD drug discovery at Scripps Research, which will continue well after the award is over. Our major planned milestone is aimed to INSPIRE program building and create team building for AD/ADRD Drug Discovery using the very considerable institutional resources at Scripps Research and its Calibr Drug Discovery Center. We are also building one of the nation’s top-ranked Graduate School programs in drug discovery via our mentoring using the faculty of Scripps’ #1/#2-ranked chemistry- biochemistry departments in the world. As proof of feasibility, of the six currently FDA-approved medicines for AD, three were developed out of the PI, Dr. Lipton’s laboratory. Via this R35 Leadership Application, Dr. Lipton will mentor others to develop AD/ADRD-related drugs acting at novel targets toward disease-modifying therapy. Specifically, Dr. Lipton will serve as research mentor for New Investigators and Early Stage Investigators (NI/ESI) in AD/ADRD drug discovery. To date, virtually all AD/ADRD therapeutics evaluated in human clinical trials have so far failed to show disease-modifying effects for AD/ADRD. For example, the lack of significant efficacy in clinical trials with Aβ-centered therapeutics to date demands a new paradigm for development of effective AD therapeutics. To overcome these significant gaps in knowledge and to advance therapies, improvements in the models and strategies by which AD/ADRD researchers function and execute need to occur. One solution to this challenge is to unite the best basic scientists with training in neuroscience, structural biology, bioinformatics and computational biology, with equally expert teams in the pharmaceutical industry trained in high-throughput screening, assay development, medicinal chemistry, chemical biology and pharmacology. With a collective and harmonized team along with significant mentoring efforts for junior faculty (NI/ESI), the PI, Dr. Lipton, has initiated three major efforts to address this unmet medical need, which will be carried out under the auspices of the current R35 Leadership Award application: · Investigation, identification and characterization of potential AD/ADRD therapeutic targets in the context of the central pathophysiological processes in AD/ADRD. · Execution of drug discovery campaigns to develop investigational new drug (IND) clinical candidates iteratively with the target elucidation efforts, while building upon Scripps drug discovery infrastructure to accomplish this. · Continue to mentor junior faculty and build a world-class graduate school around the chemical biology of drug design for AD/ADRD at Scripps (currently ranked...