# Targeting the IKK-Binding Domain of NEMO for Inhibitors Discovery

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2022 · $369,000

## Abstract

Abstract
 The NF-κB essential modulator (NEMO) is an essential component in the activation of the
canonical NF-κB pathway and exerts its function by recruiting the inhibitor of κB kinases IKKα
and IKKβ to the IKK complex. Inhibition of the interaction between the IKKα and IKKβ kinases
and NEMO is considered an attractive therapeutic avenue to the inhibition of NF-κB, due to the
pathway’s role in human diseases, encompassing inflammatory and autoimmune diseases and
cancer. The strategy was shown to be effective utilizing a peptide, corresponding to the
NEMO-binding domain of the IKKs (NBD), as an IKK complex inhibitor in in vitro and in vivo
models of disease. The overall goal of the project is the understanding of the mechanism for
NEMO inhibition and its exploitation for the development of small molecule inhibitors. The long-
term expectation of the project is to establish the structural basis for inhibitor design and the
requirements for high affinity binding and specificity. The project will evolve through three
specific aims: 1. Structural and computational methods will be utilized to characterize the
structure of NEMO-inhibitor complexes, which rely on a new construct of the IKK-binding
domain of NEMO which easily yields X-ray structures. Furthermore, the available structures of
unbound NEMO in a closed and semi-open structure will be utilized for inhibitor design. 2. The
NEMO structures will guide the rational design of peptide and small molecule inhibitors, to
develop into potent inhibitors with distinct physical and chemical properties from the NBD and
testing the potential of different binding sites for inhibition. 3. The interaction between NEMO
and inhibitors will be characterized by biochemical, biophysical and cellular methods, to
quantify the binding affinity, validate binding, identify the binding site and characterize the
binding mode and requirements. In addition, the biological evaluation in cellular model systems
of cancer that rely on NF-κB signaling for survival, will provide the rationale and justification for
future preclinical development and clinical studies. The expertise of the Investigators involved
in the research matches the multidisciplinary character of the project, with experience in assay
development and biophysical characterization, NMR-based screening and structure
determination, X-ray crystallography, peptide chemistry and synthetic medicinal chemistry,
cancer biology and anticancer drugs, and a long experience in the characterization of NEMO.
The outcome of this research will further our understanding of the requirements and
consequences of NEMO inhibition and open the way to the development of new therapies for
human disease.

## Key facts

- **NIH application ID:** 10465104
- **Project number:** 5R01GM133844-04
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** MARIA Margherita PELLEGRINI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $369,000
- **Award type:** 5
- **Project period:** 2019-09-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465104

## Citation

> US National Institutes of Health, RePORTER application 10465104, Targeting the IKK-Binding Domain of NEMO for Inhibitors Discovery (5R01GM133844-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10465104. Licensed CC0.

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