# Macrocyclic Peptidyl Inhibitors of NEMO-IKK Interaction

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2022 · $412,864

## Abstract

Project Summary
 NF-κB is a family of transcription factors that are expressed in all mammalian cell types and act as
the master regulator of the immune response. Aberrant activation of NF-κB has been implicated in
many inflammatory and autoimmune diseases, as well as cancer. NF-κB can be activated by two
different signaling pathways, the canonical (or classical) pathway and the non-canonical pathway.
Canonical NF-κB signaling involves a key interaction between inhibitor of κB (IκB)-kinase α/β
(IKKα/β) and NEMO (also called IKKγ). Inhibition of the NEMO-IKKα/β interaction thus represents an
attractive anti-inflammatory and anticancer strategy, as the inhibitor would block the NF-κB activity
induced by pro-inflammatory stimuli but not the basal NF-κB activity, which is required for normal B-
and T-cell function. Unfortunately, previous attempts to develop small-molecule inhibitors against this
intracellular protein-protein interaction have been largely unsuccessful. In this project, we will explore
cell-permeable macrocyclic peptides for inhibition of the NEMO-IKKα/β interaction. Specific Aim 1 is
to further optimize the potency, selectivity, and other drug properties of a bicyclic peptidyl inhibitor
(NI174-5; IC50 = 1.0 µM) discovered during our preliminary studies and biochemically, biologically,
and structurally (by X-ray crystallography and in silico modeling) characterize the improved NEMO
inhibitor(s). Specific Aim 2 is to determine the effect of NI174-5 (or an improved NEMO inhibitor) on
ovarian cancer stem cells (CSC) in vitro and in vivo, as well as its ability to prevent tumor relapse
following initial cisplatin treatment in an orthotopic ovarian tumor xenograft model.

## Key facts

- **NIH application ID:** 10426246
- **Project number:** 5R01CA234124-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Dehua Pei
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $412,864
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10426246

## Citation

> US National Institutes of Health, RePORTER application 10426246, Macrocyclic Peptidyl Inhibitors of NEMO-IKK Interaction (5R01CA234124-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10426246. Licensed CC0.

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