AI-driven discovery of in vivo chemical probes for understudied targets for the treatment of Alzheimer's disease and related disorders (ADRD)

Alzheimer’s disease and related dementias (ADRD) are debilitating diseases that are increasing in prevalence being the most common form of dementia worldwide. Current therapies are primarily palliative in nature except for the recent amyloid antibodies which show variable and incremental efficacy in slowing disease progression. We here apply the emerging tools of Artificial Intelligence (AI) and Machine Learning (ML) to aid in the discovery of in vivo chemical probes for understudied targets in AD research. The project is closely aligned with the NIA- funded AD Initiatives Accelerating Medicines Partnership in Alzheimer’s Disease Target Discovery and Preclinical Validation project and the Emory-Sage-SGC-JAX TaRget Enablement to Accelerate Therapy Development for AD (TREAT-AD) center. We will examine all 900 proteins currently listed on the TREAT-AD website, evaluate 15 per year using virtual screening from our compound libraries, and advance five of these through a series of SAR development activities leading to in vivo chemical probes which are made publicly available through TREAT-AD and shared with the scientific community. We will leverage validated virtual screening workflows for novel target discovery, a process for which we have extensive experience. Aim 1 is target selection closely aligned with TREAT-AD. Aim 2 is virtual screening for novel compounds with desired target binding activity. Aim 3 is assay development and testing of top hits from Aim 2 plus structural analogs. An ad hoc Target Project Team will be created for each target that emerges from Aim 2. Aim 4 incorporates novel AI-driven algorithm development and training for optimizing selective leads from Aim 3 hits. Aim 5 is medicinal chemistry refinement of the AI/ML outputs and biochemical and functional characterization of chmical hits including ADME characterization suitable for the identification of probes for in vivo studies. A Hit Review Steering Committee (HRSC) will review the hits and leads that are discovered during the course of this project to provide guidance as to design and interpretation of studies as well as which hits and chemotypes to advance further. Finally, Aim 6 is public dissemination of the structures and activities of new in vivo chemical probes for understudied targets in AD research. Small molecule chemical probes are validated for further proof of concept research if they have binding or functional activity at targets of interest to the extent of ≤100 nM (preferred) and in vivo PK in mice with a t1/2 of ≥60 mins (preferred), %F (oral bioavailability) of ≥20% and a brain:plasma ratio of ≥0.5. In summary, 15 targets per year will go into a full virtual screen. Based on the data, five targets per year will go to experimental validation and SAR development. All of the data will be released on the TREAT-AD website so others can pursue the 10 targets per year that were not followed up on. We will use modern methods in computational chemistry including AI and ML to discover and characterize new in vivo chemical probes for understudied targets in AD research. It is anticipated that these in vivo chemical probes will be widely used by researchers in the AD scientific community to understand the function of promising new targets. Project Number: 1R01AG098139-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Allen Reitz | Institution: FOX CHASE CHEMICAL DIVERSITY CENTER, INC, DOYLESTOWN, PA | Award Amount: $1,074,362 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 NV-L (52)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11293767