# Targeting Cardiovascular Disease with SIRT6 Activators

> **NIH NIH R21** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $228,750

## Abstract

Abstract
Cardiovascular and other chronic age-related diseases constitute and enormous health challenge in an aging
society, and yet therapeutics that address the age-related etiology of these diseases are lacking. The objective
of the outlined research project is to develop an activator of sirtuin 6 (SIRT6) to prevent and possibly reverse the
progression of cardiovascular and other diseases. Many studies have demonstrated the age-delaying and
cardioprotective effects of SIRT6 and the prospect of activating SIRT6 as a therapeutic modality has been well
recognized. The proposed research addresses the key limitation towards accessing such drug candidates, which
is the lack of a potent and selective lead molecule for SIRT6 activation with a favorable ADME profile. We
propose accessing such molecules in a two-step approach that consists of i) generating and screening a DNA-
encoded library custom-designed for discovering SIRT6 activators, and ii) structure-guided approaches that
translate the DNA-encoded library screening data into lead-quality compounds. Screening 250,000 compounds
specifically designed to target known allosteric sites on SIRT6 not only provides a maximum probability of
identifying lead molecules with the desired properties, but the integration of structure-guided design and focused
DNA-encoded libraries is technologically novel. The activity in vitro and in cells as well as basic pharmacokinetic
properties will be rigorously evaluated. The effectiveness of pharmaceutical SIRT6 activation will be tested in a
murine model of arterial stiffening that is directly related to several forms of cardiovascular disease. The project,
if successful, will establish the framework for developing therapeutics that directly target the causative
mechanisms of cardiovascular disease with the prospect of decreasing the morbidity and mortality of millions of
patients. Developed molecules will further allow testing pharmaceutical hypotheses in an array of other diseases
that have been linked to SIRT6 activation including neurodegeneration and cancer.

## Key facts

- **NIH application ID:** 10489674
- **Project number:** 5R21AG070740-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Raphael M. Franzini
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $228,750
- **Award type:** 5
- **Project period:** 2021-09-30 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10489674

## Citation

> US National Institutes of Health, RePORTER application 10489674, Targeting Cardiovascular Disease with SIRT6 Activators (5R21AG070740-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10489674. Licensed CC0.

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