# Project 2

> **NIH NIH U54** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2023 · $146,080

## Abstract

PIN1 is a cis-trans prolyl isomerase that controls proline-mediated phosphorylation signaling events that is
overexpressed both in pancreatic cancer cells and cancer-associated fibroblasts. PIN1 overexpression is a major
contributor to tumorigenesis, activating several oncoproteins, including proteins in the KRAS pathway, and
simultaneously inactivating several tumor suppressors. Recent studies using genetic and pharmacological
inhibitors show that PIN1 regulates key oncogenic pathways. Importantly, PIN1 promotes an
immunosuppressive/treatment-resistant TME, by up-regulating PD-L1 (programmed cell-death receptor-1) The
chemotherapy drug, gemcitabine, is frequently used in front-line treatment of pancreatic cancer. PIN1 also drives
chemotherapy-resistance by degrading the gemcitabine uptake-transporter, ENT1 (equillabrative nuclear
transporter-1) both in tumor cells and cancer-associated fibroblasts. Hence, the development of PIN1 inhibitors
could increase sensitivity of pancreatic cancer to both chemotherapy and immunotherapy. The laboratory of Dr.
Pellecchia (University of California Riverside; UCR) has developed initial PIN1 inhibitors that have promising
pharmacokinetic properties. To do this, Dr. Pellecchia used a drug discovery strategy based on a combination
of biophysical methods including 1) medicinal chemistry 2) NMR spectroscopy, 3) X-ray crystallography (Dr.
Blaha, UCR) and 4) denaturation thermal shift measurements. This structure-based design approach used to
derive innovative covalent PIN1 targeting agents that cause degradation of PIN1 in pancreatic cell lines. Guided
by our resources and preliminary data, we propose a collaboration between UCR and CoH to 1) optimize and 2)
develop a potent and selective PIN1 inhibitor for treatment of pancreatic cancer. Aim 1 will design, synthetize,
and iteratively optimize novel, drug-like PIN1 targeting agents. Aim 2 will study the mechanism of action and
efficacy of most promising agents in cellular and animal models of pancreatic cancer. We will assess the
pharmacokinetics properties (Dr. Horne and CoHCCC shared resources) of refined agents in mice and test their
efficacy in animal models of pancreatic cancer (Dr. Horne, Dr. Raoof, CoH) including orthotopic, patient derived
xenografts, and transgenic mouse models of pancreatic cancer.

## Key facts

- **NIH application ID:** 10762161
- **Project number:** 1U54CA285116-01
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Maurizio Pellecchia
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $146,080
- **Award type:** 1
- **Project period:** 2023-09-22 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10762161

## Citation

> US National Institutes of Health, RePORTER application 10762161, Project 2 (1U54CA285116-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10762161. Licensed CC0.

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