# Modulation of the Innate Immune Response by Fisetin Derivatives for the Treatment of AD

> **NIH NIH R44** · VIROGENICS, INC. · 2020 · $965,711

## Abstract

Abstract
 There are currently no drugs or other therapeutic interventions that can reverse or halt the progression of
Alzheimer's disease (AD). Age is by far the greatest risk factor for AD, and it is known from studies in both
mice and humans that neuroinflammation is increased with old age and to an even greater extent in AD.
Therefore, a drug that could reduce neuroinflammation and at the same time be neuroprotective would have an
excellent chance in the clinic. To address this problem, we devised a drug discovery program based upon a
unique set of phenotypic screens to identify small molecules which reduce the toxicities to cortical neurons that
occur with old age and which also have anti-inflammatory activity. Our initial studies using this approach led to
the identification of the flavonoid fisetin as a molecule that modulates neuroinflammation in ways that are
beneficial for altering AD progression. A series of much more potent fisetin derivatives was then synthesized
by SAR-driven iterative chemistry. Many of these derivatives maintain in vitro anti-inflammatory activity.
Importantly, the derivatives do not suffer from the intellectual property challenges of the natural product fisetin
and are covered under several pending patents held by the Salk Institute. From the 160 derivatives
synthesized, we selected the best seven derivatives that maintain the biological activities of fisetin, including its
anti-inflammatory activity, for further studies. Based on these studies, we identified CMS121 as a modulator of
neuroinflammation and a clinical candidate for the treatment of AD. Importantly, we have shown that CMS121
prevents most of the behavioral and physiological changes associated with aging and the sporadic AD
phenotype in both a transgenic AD mouse and in a novel mouse model of old age-associated sporadic AD that
accounts for 99% of human AD cases. Moreover, preliminary toxicology studies demonstrate that CMS121 has
undetectable genotoxicity. The overall goal of the research described in this application is to complete the
studies needed for an IND submission to the FDA. To do so we wish to utilize the phase IIB program which is
designed to address the funding gap between a phase II SBIR/STTR award and the external financing needed
to advance a product to commercialization. Consistent with the purpose of the Phase IIB program which was
added in recognition of the fact that most small businesses cannot afford the equipment nor the full-time
expertise required for expensive IND-enabling studies, much of the work in the proposed research plan will be
conducted by CROs. We will provide overall supervision and direction as well as coordination of the different
steps that need to be completed in order to file an IND submission. Together, these studies should place
CMS121 in an excellent position to obtain outside funding and begin phase I clinical trials.

## Key facts

- **NIH application ID:** 9964648
- **Project number:** 5R44AI104034-07
- **Recipient organization:** VIROGENICS, INC.
- **Principal Investigator:** WILLIAM C RASCHKE
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $965,711
- **Award type:** 5
- **Project period:** 2013-08-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964648

## Citation

> US National Institutes of Health, RePORTER application 9964648, Modulation of the Innate Immune Response by Fisetin Derivatives for the Treatment of AD (5R44AI104034-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9964648. Licensed CC0.

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