Small molecule modulation of S1PR signaling for the treatment of alzheimer's disease

Tiaki Therapeutics Inc. was awarded a $1,099,720 cooperative agreement from the National Institute on Aging, part of the National Institutes of Health within the Department of Health and Human Services, to support research under the Aging Research program (CFDA 93.866). The award will fund the optimization of Tiaki's lead small molecule compounds that modulate sphingosine 1-phosphate receptor signaling to treat Alzheimer's disease by reducing neuroinflammation. Specifically, the funding will support further improving the bioactivity and physicochemical properties of lead compounds, confirming anti-inflammatory activity in neuroinflammation assays, and obtaining toxicology and safety profiles to advance a clinical candidate compound toward future clinical studies modulating neuroinflammatory Alzheimer's disease through microglial S1PR modulation. The award period is from September 5, 2021 through April 25, 2022.

Abstract

Alzheimer's disease (ad) is currently the sixth leading cause of death in the united states. A disease- modifying therapeutic does not yet exist for ad and currently represents a significant, unmet medical need. Tiaki therapeutics has discovered a signature of neuroinflammatory disease biology that is present in several neurodegenerative disorders, including a neuroinflammatory subpopulation of ad patients. Neuroinflammation plays a substantial role in the development and progression of ad and is increasingly recognized as a third disease pathology. Dysregulation of sphingolipid metabolism and signaling is a significant contributor to the shared neuroinflammatory disease biology. Tiaki has created an EX vivo systems biology assay that models the same neuroinflammatory disease biology seen in patients for use in both target validation and as a functional assay to support drug discovery. Eight targets were assessed and only antagonism of sphingosine 1-phosphate receptor consistently and robustly reversed the disease-associated neuroinflammatory signature. Microglia, the resident innate immune cells of the CNS, subserve a critical role in maintaining homeostasis in under normal conditions. However, under extreme circumstances microglia can be induced to enter a toxic, pro-inflammatory state. Sphingosine 1-phosphate (S1P) is a bioactive lipid created through the action of sphingosine kinases (sphks) and signals through a family of gpcrs (S1PR1-5). Exposure of microglia to pro- inflammatory stimuli results in an increase in activity of sphks, production and release of S1P and subsequent activation of S1PRS, which ultimately drives NF-b-mediated transcription and production of pro-inflammatory cytokines. This feedback loop establishes a self-sustaining cycle of local microglial activation that can mediate propagation of pro-inflammatory signaling. We hypothesize that alleviation of this pro-inflammatory feedback loop will restore a CNS environment where microglial protective functions are favored, thereby decreasing neurotoxicity and promoting neuronal homeostasis. The S1PR of interest is expressed on microglia and the expression of this gene is dysregulated in ad patient transcriptomes. Tiaki's lead small molecule reverses the neuroinflammatory signature in the EX vivo slice culture assay and in vivo in a bespoke animal model that recapitulates the neuroinflammatory changes observed in patient transcriptomic data. Using a homology model and targeted analogs, we have established a robust structure-activity-relationship for modulation of the specific S1PR. Tiaki proposes further optimization and development of this lead molecule to enable clinical studies investigating the potential for specific modulation of microglial S1PRS in treating ad. To this end, we propse to: 1) optimize the bioactivity and physicochemical properties of our lead compounds, 2) confirm anti- inflammatory activities of lead compounds in neuroinflammation assays, and 3) obtain toxicological and safety profiles of the microglial S1PR modulators. At the end of this project, tiaki will have a clinical candidate compound and an IND supporting future clinical studies for the modulation of neuroinflammatory ad.