# Development of non-ATP competitive chemical biology probes to elucidate mechanisms of PLK1 activation and stability.

> **NIH NIH R21** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2022 · $170,662

## Abstract

Polo-like kinase 1 (PLK1) is a central player in regulating entry into and progression through
mitosis. Many studies have validated PLK1 as an anti-tumor drug target, and its inhibition is
potently anti-proliferative to cancer cells. We have discovered a series of compounds that bind
potently to the polo-box domain of PLK1 named abbapolins through a cryptic pocket and which
induce proteasome mediated degradation of the PLK1 protein in a dose dependent manner
without the addition of a ligand to recruit an E3 ligase to promote ubiquitination (PROTAC
approach). The abbapolins are also able to inhibit the phosphorylation of a PLK1 specific marker
while potently inhibiting the proliferation of prostate cancer cell lines. As a result of these exciting
observations, we propose to further develop these inhibitors as potent PBD inhibitors and
degraders of PLK1 while using them as chemical biology probes to provide new insights the
regulation of PLK1 activity through conformational change, substrate recognition and proteasomal
stability. Our experiments will therefore shed new light into the regulation of PLK1 at the cellular
level while generating novel data on the molecular determinants and features important for
inhibition. In turn this may provide understanding of the factors contributing to the lack of clinical
activity for the ATP competitive inhibitors of the PLK mitotic kinases while laying the groundwork
for preclinical and clinical development the abbapolins as cancer therapeutics with a unique
mechanism of action.

## Key facts

- **NIH application ID:** 10437922
- **Project number:** 5R21CA263359-02
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Campbell McInnes
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $170,662
- **Award type:** 5
- **Project period:** 2021-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10437922

## Citation

> US National Institutes of Health, RePORTER application 10437922, Development of non-ATP competitive chemical biology probes to elucidate mechanisms of PLK1 activation and stability. (5R21CA263359-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10437922. Licensed CC0.

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