STOP‐AD portal: Selecting the optimal pharmaceutical for preclinical drug testing in Alzheimer's disease

Abstract

We propose an unbiased methodology to rank compounds for advancement into comprehensive preclinical testing for Alzheimer's disease (AD). Translation of compounds to the clinic in AD has been hampered by poor predictive validity of models, compounds with limited pharmaceutical properties, and studies that lack rigor. To overcome this, MODEL‐AD's Preclinical Testing Core developed a standardized pipeline for assessing efficacy in AD mouse models. We hypothesize that rank‐ordering compounds based upon pharmacokinetic, efficacy, and toxicity properties in preclinical models will enhance successful translation to the clinic. Previously compound selection was based solely on physiochemical properties, with arbitrary cutoff limits, making ranking challenging. Since no gold standard exists for systematic prioritization, validating a selection criteria has remained elusive. The STOP‐AD framework evaluates the drug‐like properties to rank compounds for in vivo studies, and uses an unbiased approach that overcomes the validation limitation by performing Monte‐Carlo simulations.Highlights Promising preclinical studies for AD drugs have not translated to clinical success. Systematic assessment of AD drug candidates may increase clinical translatability. We describe a well‐defined framework for compound selection with clear selection metrics.

Meeting report of the fifth annual workshop on Principles and Techniques for Improving Preclinical to Clinical Translation in Alzheimer's Disease Research

“…Given the intensive resources required for the comprehensive drug screening conducted by the PTC, as described by Dr. Territo, the team has developed a framework that provides an unbiased ranking of compounds nominated by the community for selection and prioritization. 48 Researchers are encouraged to submit nominations for compounds to be screened by accessing the following portal: https://stopadportal.synapse.org. Taken together, there are significant resources and infrastructure that are available to researchers including the resources of the NIAfunded R13 mechanism supporting this workshop.…”

“…Paul Territo and Stacey Rizzo presented details on the Selecting The Optimal Pharmaceutical for preclinical drug testing in AD (STOP‐AD) portal. 48 The MODEL‐AD PTC has established a rigorous and unbiased multi‐tiered screening strategy for evaluating compounds as potential therapeutic interventions for AD. 9 The PTC pipeline prioritizes translational assessments of PK and PD measures including positron emission tomography (PET)/computed tomography (CT) and magnetic resonance imaging (MRI), as well as behavioral assessments and molecular profiling in response to drug treatment in mouse models validated by MODEL‐AD at minimal costs to the investigator (Figure 2 ).…”