# Synergistic Inhibitors of CREB-mediated Gene Transcription

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $320,081

## Abstract

Public Abstract
The goal of this application is to develop synergistic inhibitors of CREB-mediated gene
transcription. Cyclic-AMP-response element binding protein (CREB) is a 43 kD nuclear
transcription factor. Its transcription activity is critically dependent on phosphorylation on
Ser133 to be induced by extracellular signals including growth factors and hormones.
CREB is overexpressed and/or overactivated in tumor tissues of different organs
compared to normal tissue. CREB's transcription activity is activated upon
phosphorylation at Ser133 by a variety of protein kinases including protein kinase A
(PKA), mitogen-activated protein kinases (MAPKs), protein kinase B (PKB/Akt) and
protein ribosomal S6 kinase (pp90RSK). Once phosphorylated, CREB can bind with
CREB-binding protein (CBP) and its paralog p300 to recruit other components in the
transcriptional machinery to the CREB promoter to initiate CREB-dependent gene
transcription. CREB's phosphorylation in normal cells is tightly regulated and very
dynamic. Until now, three protein phosphatases have been identified to be able to
remove the phosphate from CREB to attenuate its transcription activity. They are protein
phosphatase 1 (PP1), protein phosphatase 2A (PP2A) and phosphatase and tensin
homolog (PTEN). Mechanistically, the kinases are often overactivated in cancer cells
while the phosphatases are often inactivated in cancer cells. As a consequence, CREB
is often overactivated in cancer cells compared to normal cells. Higher expression and/or
activation of CREB is associated with poorer prognosis in cancer patients. Preclinical
studies have validated CREB as an appealing target for various cancers. We recently
identified various chemotypes as small molecule inhibitors of CREB or potentiators to
exhibit synergistic activity in inhibiting CREB-mediated gene transcription. In this
application, we will further develop these inhibitors and potentiators as synergistic
inhibitors of CREB-mediated gene transcription. We will further study their mechanism of
action and synergistic anti-breast cancer activity in vitro and in vivo. Accomplishing the
proposed studies will provide novel insights into the mechanism of CREB regulation and
provide potential cancer therapeutics.

## Key facts

- **NIH application ID:** 10464627
- **Project number:** 2R01GM122820-05
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Xiangshu Xiao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $320,081
- **Award type:** 2
- **Project period:** 2017-04-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464627

## Citation

> US National Institutes of Health, RePORTER application 10464627, Synergistic Inhibitors of CREB-mediated Gene Transcription (2R01GM122820-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10464627. Licensed CC0.

---

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