Design and Synthesis of FDI-6-Based Hydrophobic Tag Degraders Targeting FOXM1

Author

Callie J. Martin, University of Nebraska Medical CenterFollow

ORCID ID

0009-0009-4180-5191

Graduation Date

Summer 8-2025

Document Type

Thesis

Degree Name

Master of Science (MS)

Programs

Cancer Research

First Advisor

Amarnath Natarajan (Chair)

Second Advisor

Adam Karpf

Third Advisor

Joyce Solheim

Abstract

Forkhead box M1 (FOXM1) is a transcription factor overexpressed in numerous human cancers, and this is often associated with a poor prognosis. FOXM1 regulates transcription by binding to target gene promoters and interacts with key oncogenic pathways. Previously, small molecule inhibitors have been used to target FOXM1 by disrupting DNA binding, with FDI-6 being the first selective inhibitor reported. However, FOXM1 has functions besides DNA binding, indicating the need for an alternate targeting approach to eliminate FOXM1. Targeted protein degradation, including PROTACs and HyT degraders, has emerged as a viable approach to degrade target proteins. An FDI-6-based PROTAC for FOXM1 has been reported, leading us to hypothesize that an FDI-6-based HyT degrader could also regulate FOXM1 levels. By replacing the cereblon ligand in the PROTAC with a hydrophobic group, we aim to reduce off-target effects and increase specificity for FOXM1. HyT degraders bind to the surface of target proteins, exposing hydrophobic regions that can mimic the characteristics of misfolded proteins, which in turn triggers the protein quality control system to induce proteasomal degradation. To test our hypothesis, we designed and synthesized eight FDI-6-based HyT degraders using norbornene and adamantane as the hydrophobic groups. These degraders were purified by flash chromatography and characterized by ¹H and ¹³C NMR spectroscopy. Their final purity (>95%) was confirmed using high-performance liquid chromatography (HPLC). Compound 6a was tested against OVCAR4 ovarian cancer cells. Target engagement studies showed a decrease in FOXM1 protein levels, suggesting that HyT degraders may be a promising approach for degrading FOXM1.

Comments

2025 Copyright, the authors

Recommended Citation

Martin, Callie J., "Design and Synthesis of FDI-6-Based Hydrophobic Tag Degraders Targeting FOXM1" (2025). Theses & Dissertations. 959.
https://digitalcommons.unmc.edu/etd/959