# Nautral products for targeting Skp2 in cancer interception

> **NIH NIH UG3** · UNIVERSITY OF CALIFORNIA-IRVINE · 2024 · $333,625

## Abstract

Project Summary
Prostate cancer (PCa) is the second most common cancer in American men and is responsible for 3% of total
deaths and 10% of deaths by cancer. Most patients experience a slow-progressing disease and are assigned
to active surveillance. These patients are spared immediate radical prostatectomy (RP) or radiation that is
used for patients that have more advanced disease. Because assignment to active surveillance is imperfect,
some patients are unnecessarily overtreated, with the burdens of unnecessary side effects, cost, and lower
quality of life, whereas a few patients that need prompt radical treatment may experience delays. The limited
treatment options available for aggressive disease usual fail within a few years. Thus, there is an unmet clinical
need for low toxicity preventive/interceptive agents or natural products that prevent PCa progression either
during active surveillance or after RP or radiation treatment.
S phase kinase-associated protein 2 (Skp2) is a putative oncogene that targets several tumor suppressors for
degradation. The Skp2 gene is amplified in several human cancers. In PCa, Skp2 is overexpressed in pre-
malignant high-grade prostatic intraepithelial neoplasia (HG-PIN) and in primary tumors, suggesting a role in
the early stages of PCa. Skp2 deletion blocks tumorigenesis in Rb1, p53, or Pten deficient mouse models,
suggesting that Skp2 may serve as an “Achilles' heel” drug target against pRb, p53 and/or Pten-deficient
cancer. However, inhibitors that disrupt Skp2 protein-protein interactions or cause degradation through the
proteolysis targeting chimera (PROTAC) have had limited success. Thus, we propose to instead screen
directly for natural products that target Skp2 for degradation. In a collaboration with the National Center for
Advancing Translational Sciences (NCATS), we will use 500,000 natural product samples that are known to
include highly diversified chemotypes with cancer-preventive properties. To implement the screen, we have
developed a cell-based luciferase assay for degradation of Skp2 and several other resources including our
large PCa patient cohort, our prostate-specific human Skp2 knock-in mouse model of early prostate
carcinogenesis, our PCa patient-derived organoid cultures, and patient-derived xenograft (PDX) models.
In Specific Aim 1 (UG3) we will optimize our cell-base luciferase assay, develop a prototype HTS assay for
screening skp2 degraders, and perform mechanistic studies of products that have potential utility. In Specific
Aim 2 (UG3) we will quantitate Skp2 protein in PCa progression. This is a step towards identifying patients that
would benefit from interception via a Skp2 degrader, which will be important for developing a novel clinical trial.
In Specific Aim 3 (UH3) we will complete a full-scale HTS of up to 500,000 natural products with NCATS. We
will perform activity-based characterization and bioassay-directed isolation, structural elucidation, and perform
mechanistic stud...

## Key facts

- **NIH application ID:** 10878538
- **Project number:** 1UG3CA290368-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Xiaolin Zi
- **Activity code:** UG3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $333,625
- **Award type:** 1
- **Project period:** 2024-06-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878538

## Citation

> US National Institutes of Health, RePORTER application 10878538, Nautral products for targeting Skp2 in cancer interception (1UG3CA290368-01). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10878538. Licensed CC0.

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