# Core C - Drug Discovery and Development Core (DDDC)

> **NIH NIH P01** · MAYO CLINIC ROCHESTER · 2024 · $547,454

## Abstract

CORE C: Drug Discovery and Development Core – SUMMARY
The overall goal of this multi-disciplinary, multi-site PPG application is to build a firm foundation of discovery
science in cellular senescence that leads to a pipeline of therapeutic strategies that slow or prevent age-
associated diseases. Each of the three PPG Projects focus on the role of senescent cells in specific age-related
health outcomes: Project 1, Skeletal Fragility (Khosla/Monroe); Project 2, Skeletal Muscle Loss and Dysfunction
(LeBrasseur) and Project 3, Brain aging (Jurk). To establish cause and effect, each project will use genetic and
pharmacologic approaches to ablate senescent cells. In addition, each of these projects will test the efficacy of
senotherapeutic compounds (drugs that induce apoptosis specifically of senescent cells [senolytics] or suppress
markers of senescence, in particular SASP [senomorphics]) in treating their health outcome focus. The
identification and characterization of effective senotherapeutics for different lineages of senescent cells will be
performed by the Drug Discovery and Development Core C (DDDC), working with PIs of each of the three
projects and three additional cores. Importantly, the collaborative published and preliminary data from PPG
members establishes that no single senotherapeutic is effective in all senescent cell types. Thus, it is imperative
to have a centralized Core as part of this PPG to continue to develop and utilize standardized measures of
senescence and senotherapeutic activity to identify the most efficacious drugs or drug combinations. During the
previous funding period, the DDDC identified and optimized multiple types of senotherapeutics including
improved analogs of fisetin, a senolytic natural lipid that induces senescent cell death via ferroptosis, zoledronic
acid and optimized analogs, several natural products including tomatidine and multiple drugs targeting epigenetic
regulators. These drugs were identified and validated in our established workflow of screening for activity in
primary cells or cell lines from multiple species, testing in vivo in a rapid model of accelerated senescence/aging,
followed by testing in naturally aged mice. In addition, we identified multiple miRNAs able to drive or prevent
senescence as well as used bioinformatic analysis of the targets of senescence-associated miRNAs to identify
new senotherapeutic targets. Furthermore, we have used machine learning approaches to identify a novel class
of natural senolytics. Finally, we have collaborated with Dr. Daohong Zhou to test the efficacy of optimized
PROTACs targeting Bcl-2 family members and are co-developing novel PROTACs. Importantly, using
scRNAseq of senescent cells, we have identified subsets of SnCs with differential sensitivity to these senolytics
including differential sensitivity of p16INK4a and p21CIP1-positive SnCs. Thus, the role of the DDDC within this
multi-site PPG is to continue to develop and implement assays for measuri...

## Key facts

- **NIH application ID:** 10845137
- **Project number:** 2P01AG062413-06
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Paul D. Robbins
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $547,454
- **Award type:** 2
- **Project period:** 2019-06-01 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10845137

## Citation

> US National Institutes of Health, RePORTER application 10845137, Core C - Drug Discovery and Development Core (DDDC) (2P01AG062413-06). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10845137. Licensed CC0.

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