# Direct protein phosphatase 2A (PP2A) activators as novel Alzheimer’s Disease (AD) therapeutics

> **NIH NIH R44** · ATUX ISKAY GROUP LLC · 2024 · $1,688,077

## Abstract

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder with symptoms usually manifesting later
in life in patients over 65 years of age, so called late-onset or sporadic AD. The World Alzheimer’s Report
projects that AD related dementia will rise to 76 million cases by 2030 and 132 million cases by 2050. In the
US alone it is estimated that in 2018, Alzheimer’s and other dementias cost the nation $277 billion. By 2050,
costs could rise as high as $1.1 trillion. Novel therapeutics that prevented or even slowed AD progression
would be of immense economic importance and benefit a huge, and growing, number of patients and their
families. Atux Iskay LLC proposes to develop a novel class of compounds as AD therapeutics that act by
increasing, and normalizing, abnormally suppressed protein phosphatase 2A (PP2A) activity in AD, and
thereby directly target the underlying pathology of the disease. Atux Iskay LLC proposes to develop lead
compounds that bind and allosterically activate PP2A, thereby suppressing tau phosphorylation, amyloidogenic
APP processing and neuroinflammation associated with established disease. The lead compound is orally
bioavailable and partitions into the CNS after oral dose. Prototype compounds are active in cellular models of
tau-phosphorylation and Ab secretion, show neuroprotective effects in ex vivo electrophysiology models of
synaptic plasticity and are active in an in vivo rat model of AD where they ameliorate tau and Ab pathologies
and rescue behavioral and cognitive deficits induced in the disease model. The objectives of the project are
 Aim 1. Synthetic and process chemistry on pyran sulfonamide lead. A. Scale-up and resolution
(into (+)- and (-)-enantiomers) of lead compound, ATUX-5800, for pilot toxicology and efficacy studies. B.
Synthetic route scouting for GMP process synthesis of resolved ATUX-5800. Aim 2. Pilot safety assessment
on resolved enantiomer of ATUX-5800. A. Rat PK on resolved isomers of ATUX-5800. B. In vitro, off target,
profile on resolved isomers of ATUX-5800. C In vitro safety assessment on (+)-ATUX-5800 or (-)-ATUX-5800.
D. In vivo (rat) pilot toxicology on (+) or (-)-ATUX-5800. Aim 3. In vivo efficacy on (+) or (-)-ATUX-5800 in
5xFAD transgenic mouse model and assessment of neuroinflammation. Aim 4. Structural biology and
back-up medicinal chemistry. A. Novel modifications of ATUX-5800 structural type. B. Medicinal chemistry
to identify development candidate from ATUX-6156 (sulfonyl urea) structural type. C. Structural biology to
obtain PP2A (A and AC) with bound lead activators ((+) and (-)-ATUX-5800) and back-ups.
 Successful completion of the Phase 2 SBIR Aims will position a lead compound for GMP synthesis and
IND enabling GLP toxicology. The overall objective are new, first in class, disease modifying AD therapeutics
that will benefit AD patients and reduce the enormous and growing burden of Alzheimer’s Disease Related
Dementia.

## Key facts

- **NIH application ID:** 10820051
- **Project number:** 2R44AG071040-02
- **Recipient organization:** ATUX ISKAY GROUP LLC
- **Principal Investigator:** Michael Ohlmeyer
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,688,077
- **Award type:** 2
- **Project period:** 2020-09-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10820051

## Citation

> US National Institutes of Health, RePORTER application 10820051, Direct protein phosphatase 2A (PP2A) activators as novel Alzheimer’s Disease (AD) therapeutics (2R44AG071040-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10820051. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*