# Targeting the Sam68-stimulated PARP1 activation for cancer treatment

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $364,073

## Abstract

Project Summary
 The inhibition of poly(ADP-ribose) polymerase 1 (PARP1) protein has emerged as a promising
therapeutic treatment for several types of cancers. However, the current classes of PARP1 inhibitors are all
derivatives of nicotinamide, based on the strategy of competitive binding against nicotinamide. Because the
PARP1-catalyzed PARylation is critical for many cellular processes, therapeutic targeting of PARP1 in
cancerous cells with current classes of PARP1 inhibitors could negatively affect many cell functions in normal
cells. There is an urgent clinical need for improving the inhibitor specificity for PARP1 and lowering the off-
target effects and toxicity for better therapeutic value and modalities. However, the rapid recruitment of
PARP1 to sites of DNA lesions (within milliseconds) and the vigorously synthesized PAR chains make it
difficult to elucidate the precise stimulatory and regulatory mechanisms on PARP1 activation. We recently
discovered that Src-associated-substrate-during-mitosis-of-68kDa (Sam68) plays an important role in
stimulating the DNA damage-specific PARP1 activation, which suggests that targeting the Sam68-stimulated
PARP1 activation could be a novel strategy to develop a new category of PARP1 inhibitors. The objective of
our research is to identify specific molecule inhibitors of the Sam68-stimulated PARP1 activation via a high
throughput screening, and our hypothesis is that these inhibitors would alleviate DNA damage-triggered
PARP1 activation thus being potential pharmacological agents for treating cancers. We have developed a
novel ELISA-based assay suitable for screening of small molecule libraries. In this proposed research, we will
conduct high throughput screening to identify small molecule compounds inhibiting the Sam68-stimulated
PARP1 activation. We will employ interdisciplinary approach combining biochemical, biophysical, and
molecular experiments, cellular assays, and imaging methods to validate the screening hits and to identify
high quality small molecule inhibitors of Sam68-PARP1 interaction. Activity of the most potent compounds will
be evaluated in a panel of cell-based and mouse model experiments to assess their capability to inhibit the
survival and development of colon cancer cells. Our project represents a very innovative strategy to inhibit
PARP1 activity through blocking the Sam68-conferred stimulatory mechanism. At the conclusion of these
studies, we expect to identify highly valuable compounds that can serve as chemical probes suitable for
further development into potent PARP1 inhibitors for cancer therapeutics. Additionally, discovery of these
inhibitors will greatly facilitate our research on the regulation and function of the Sam68-stimulated PARP1
activation under normal and disease conditions.

## Key facts

- **NIH application ID:** 10852804
- **Project number:** 5R01CA244350-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Fengyi Wan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $364,073
- **Award type:** 5
- **Project period:** 2020-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10852804

## Citation

> US National Institutes of Health, RePORTER application 10852804, Targeting the Sam68-stimulated PARP1 activation for cancer treatment (5R01CA244350-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10852804. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*