# A Cytochrome P450 Therapeutic Space for Tauopathies

> **NIH NIH R56** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $801,925

## Abstract

A Cytochrome P450 Therapeutic Space for Tauopathies
Project Summary
 In the 30 years since Tau was first identified as a key constituent of neurofibrillary tangles—and
subsequently a causative agent of neurodegeneration—the Tauopathy field has made important strides in
understanding how abnormal forms of Tau protein lead to damage. Tau interacts in complex ways with other
cellular constituents and with surrounding cells within the brain. This complexity makes developing tauopathy
therapeutics especially challenging. Currently there are no therapies that strongly alter disease progression:
approved treatments such as cholinesterase inhibitors and the NMDA receptor antagonist memantine show
modest symptomatic benefit in patients with early- to mid-stage Alzheimer’s Disease. New efforts include
reducing Tau mRNA expression, reducing insulin-associated metabolic deficits, addressing abnormal Tau
phosphorylation and, in recent clinical trials, targeting the spread of pathogenic Tau protein with
immunotherapy. To date, these approaches have yielded limited efficacy,
 Pathophysiological changes in the brain precede cognitive impairment by years or even decades,
presenting a broad temporal window for treatment. Tools including PET, chemical tracers and mass
spectrometry assays are being developed to detect prodromal pathogenic Tau isoforms in situ. Focusing on
Mendelian forms of tauopathy presents a still broader temporal window for treatment. One promising approach
to reducing long-term toxicity is targeted therapies, for example against Tau protein itself. However, Tau
protein is fundamental to a cell’s physiology and the therapeutic window of Tau-specific therapies may prove
limited.
 Our laboratories are working to create an integrated approach to both understand the biology of
tauopathies and to develop new lead compounds. Regarding the latter we are using the Drosophila TauR406W
platform as a whole animal model to identify drugs that can reduce Tau-dependent neuronal damage. An
especially promising hit is the FDA approved drug Anastrozole, an inhibitor of the cytochrome P450
Aromatase. We further demonstrated the effectiveness of Anastrozole to reduce dysfunction in an iPSC-
derived TauR406W model. Remarkably, this Tau rescue did not dependent on Anastrozole’s inhibition of
Aromatase, indicating Anastrozole is acting through off-target activities, suggesting the potential for an
improved Anastrozole analog. We propose to use our novel fly/chemistry platform to ‘evolve’ an improved
Anastrozole analog (‘anastrolog’) that better addresses Tau-mediated damage in the context of the whole
animal while retaining at least some of Anastrozole’s favorable properties.

## Key facts

- **NIH application ID:** 10461317
- **Project number:** 1R56AG066712-01A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Ross Leigh Cagan
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $801,925
- **Award type:** 1
- **Project period:** 2021-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10461317

## Citation

> US National Institutes of Health, RePORTER application 10461317, A Cytochrome P450 Therapeutic Space for Tauopathies (1R56AG066712-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10461317. Licensed CC0.

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