# Targeting Hsp60 to Inhibit CREB-mediated Gene Transcription

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $323,400

## Abstract

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 cues including
growth factors and hormones. CREB is overexpressed and/or overactivated in tumor tissues of different cancer
types compared to adjacent normal tissue. The goals of this application are to identify small molecule inhibitors
of CREB (cyclic-AMP-response element binding protein)-mediated gene transcription and understand their
mechanism of action as potential anti-cancer agents. Upon stimulation by extracellular cues, CREB is
phosphorylated at Ser133 that promotes its association 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. Many oncogenic kinases including protein kinase A (PKA), mitogen-activated protein
kinases (MAPKs), protein kinase B (PKB/Akt) and protein ribosomal S6 kinase (pp90RSK) can phosphorylate
Ser133 in CREB. These kinases are often overactivated in cancer cells. On the other hand, three protein
phosphatases, protein phosphatase 1 (PP1), protein phosphatase 2A (PP2A) and phosphatase and tensin
homolog (PTEN), can dephosphorylate CREB to attenuate CREB-mediated gene transcription. These
phosphatases are often inactivated or deleted in cancer cells. Because of this dual regulation of CREB's
transcription activity, CREB has been frequently observed to be overactivated in cancer cells. Furthermore,
overactivation of CREB inversely correlates with cancer patients survival. Therefore, CREB is intimately
implicated in tumorigenesis and has been proposed as a valuable target for developing novel cancer
therapeutics. Potentially, targeting CREB can simultaneously shut down multiple oncogenic pathways,
providing a novel type of cancer therapeutics with delayed or no resistance. We recently designed and
synthesized a potent CREB inhibitor, 666-15, with efficacious in vitro and in vivo anti-cancer activity. In this
application, we will further study 666-15 to understand its mechanism of action and structure-activity
relationship (SAR). To accomplish these goals, the following three specific aims will be addressed: 1) To
identify the direct molecular target(s) of 666-15; 2) To investigate the mechanisms by which Hsp60 regulates
CREB's transcription; 3) To identify derivatives of 666-15 with improved physicochemical properties.

## Key facts

- **NIH application ID:** 9869015
- **Project number:** 5R01GM122820-04
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Xiangshu Xiao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $323,400
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869015

## Citation

> US National Institutes of Health, RePORTER application 9869015, Targeting Hsp60 to Inhibit CREB-mediated Gene Transcription (5R01GM122820-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9869015. Licensed CC0.

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