# Mechanism of Action of a Novel Golgi-Targeted Anti-Cancer Agent

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $733,096

## Abstract

Mechanism of Action of a Novel Golgi-Targeted Anti-Cancer Agent
PROJECT SUMMARY
To cure cancer we need new, actionable targets for therapeutics that are orthogonal to current treatment
strategies to enable new, combinatorial treatment regimens. The Golgi GOLPH3 pathway has emerged as an
attractive target. Genes encoding GOLPH3 pathway proteins (GOLPH3, MYO18A, PITPNC1, and PI4KB)
have all been identified as frequently amplified and over-expressed in common human cancers, acting to
drive cancer (including lung, breast, colorectal, and prostate cancers). Furthermore, the function of the
GOLPH3 pathway is unique among known cancer promoting genes in that the GOLPH3 pathway functions in
vesicle exit from the Golgi for trafficking to the plasma membrane. Genetic interference with the GOLPH3
pathway (including depletion of PI4P, GOLPH3, MYO18A, or PI4KIII?) kills cancerous cells in culture and in
vivo, while relatively sparing normal cells. Therefore, the GOLPH3 pathway is an attractive target for novel
therapeutics. We have identified a small molecule inhibitor of the GOLPH3 pathway using a high-content,
image-based, phenotypic, high-throughput screen. This compound acts on MYO18A to impair Golgi GOLPH3
pathway function and to preferentially kill cancerous cells. Here, we propose experiments to determine the
mechanism of action of this small molecule by identifying the direct, mechanistic target. Thus, we will provide
new insight into mechanisms of oncogenic transformation by the GOLPH3 pathway, regulation of the
GOLPH3 pathway, and enable further medicinal chemistry for hit-to-lead optimization with the goal of
developing a first in class therapeutic agent.

## Key facts

- **NIH application ID:** 10247801
- **Project number:** 5R01CA254397-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** SETH J FIELD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $733,096
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247801

## Citation

> US National Institutes of Health, RePORTER application 10247801, Mechanism of Action of a Novel Golgi-Targeted Anti-Cancer Agent (5R01CA254397-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247801. Licensed CC0.

---

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