# A screen for small molecule inhibitors of CCF to suppress senescence-associated inflammation

> **NIH NIH R21** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2021 · $243,750

## Abstract

PROJECT SUMMARY
Cellular senescence is a bona fide tumor suppression mechanism but also a cause of cell and tissue aging.
Senescence is caused by a range of cellular stresses and characterized by an irreversible proliferation arrest
and a potent pro-inflammatory phenotype, the senescence-associated secretory phenotype (SASP).
Senescence-associated proliferation arrest and SASP cooperate in tumor suppression, by arresting
proliferation of damaged pre-malignant cells and promoting immune clearance of the damaged cells. However,
over the longer term, as a source of chronic inflammation, SASP also promotes tissue aging and disease.
Consequently, there is currently much effort devoted to development of pharmacologic approaches to eliminate
senescent cells to promote healthy aging. However, these so-called senolytic drugs tend to show unwanted
toxicities. An alternative, inherently less toxic approach, is to specifically inhibit the pro-aging chronic SASP.
Evidence indicates that this can be achieved without impairing tumor suppressive senescence-associated
proliferation arrest.
Towards an understanding of SASP and targets for its inhibition, we recently showed that senescent cells shed
fragments of nuclear chromatin into the cytoplasm, so-called cytoplasmic chromatin fragments (CCF), via a
nucleus-to-cytoplasmic blebbing process. CCF initiate SASP in senescent cells, via activation of the anti-viral
cytoplasmic DNA sensing apparatus to activate NFkB and hence SASP. Preliminary data indicate that
formation of CCF is triggered by dysfunctional mitochondria which signal to the nucleus via a retrograde
mitochondrial ROS-JNK kinase-53BP1 pathway to nuclear MRE11 exonuclease, whose activity is required for
CCF formation. Accordingly, inhibitors of mitochondrial ROS, JNK, MRE11 and HDAC inhibitors (which appear
to act indirectly by improving mitochondria function) all suppress CCF and SASP. To identify additional tool
compounds to probe the mechanism of CCF formation and/or approved drugs as candidates for repurposing
as anti-SASP/pro-healthy aging interventions, we have established an automated high content screen for
inhibitors of CCF. We will screen focused collections of mechanistically well-defined small molecules and drug
repurposing libraries to identify and validate novel inhibitors of CCF and SASP. Completion of these Specific
Aims will identify valuable tool compounds for further mechanistic investigation of CCF and SASP, and also
identify lead compounds for repurposing as anti-SASP/pro-healthy aging interventions in humans.

## Key facts

- **NIH application ID:** 10236352
- **Project number:** 5R21AG068651-02
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** PETER D. ADAMS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $243,750
- **Award type:** 5
- **Project period:** 2020-08-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10236352

## Citation

> US National Institutes of Health, RePORTER application 10236352, A screen for small molecule inhibitors of CCF to suppress senescence-associated inflammation (5R21AG068651-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10236352. Licensed CC0.

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