# Targeting Metal-Dependent Epigenetic Modulators via MetalloPROTACs

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $159,260

## Abstract

Project Summary. While recent efforts have identified the need for methodologies capable of inactivating
oncoproteins, current intervention strategies have left much of the proteome “undruggable.” In response the
NCI has recognized this challenge as outlined in PAR-22-216 by incentivizing the development of new
molecular targeting agents based on specific signaling pathways activated during the process of tumorigenesis
or tumor progression. This program proposes an important next step in reaching these goals by providing a
platform for the rapid development and characterization of heterobifunctional molecules capable of inducing
degradation of cancer related metalloenzymes with new molecular targeting agents. In this program, our team
will develop proteolysis targeting chimeras (PROTACs) containing state-of-the-art metal-binding
pharmacophores (MBPs) with the ultimate goal of achieving isoform-selective degradation of jumonji C-domain
containing lysine demethylases. Current strategies to inhibit conserved catalytic domain Jumonjis (JMJCs)
involve targeting the α-ketoglutaric acid (2OG) substrate-accepting active site of JMJCs with inhibitors that can
coordinate to the iron ion in the active site. Targeting the histone-binding helper domain of JMJCs generates
additional isoform selectivity. However, no inhibitor has been shown to be selective for only one isoform of
JMJCs. We have chosen to take a targeted degradation approach in order to increase the surface area of the
peripheral interaction by recruiting an E3 ligase. This program will demonstrate how the potential protein-
protein interaction induced by these chimeras can be leveraged to induce selective degradation of
metalloproteins (`MetalloPROTACs') through rational MBP and linker design and will serve as a platform for the
study of cancer biology, as well as laying the foundation for future development of therapeutic agents.

## Key facts

- **NIH application ID:** 10867489
- **Project number:** 5R21CA273632-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Michael D. Burkart
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $159,260
- **Award type:** 5
- **Project period:** 2023-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867489

## Citation

> US National Institutes of Health, RePORTER application 10867489, Targeting Metal-Dependent Epigenetic Modulators via MetalloPROTACs (5R21CA273632-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10867489. Licensed CC0.

---

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