NF-?B 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-?B has been implicated in many inflammatory and autoimmune diseases, as well as cancer. NF-?B can be activated by two different signaling pathways, the canonical (or classical) pathway and the non-canonical pathway. Canonical NF-?B signaling involves a key interaction between inhibitor of ?B (I?B)-kinase ?/? (IKK?/?) and NEMO (also called IKK?). Inhibition of the NEMO-IKK?/? interaction thus represents an attractive anti-inflammatory and anticancer strategy, as the inhibitor would block the NF-?B activity induced by pro-inflammatory stimuli but not the basal NF-?B 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-IKK?/? 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 M) 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.

Public Health Relevance

NF-?B is the master regulator of the immune response and its aberrant activation is associated with many inflammatory diseases, autoimmune diseases, and cancer. Inhibitors against the NEMO- IKK interaction is expected to block the NF-?B activity induced by pro-inflammatory stimuli and provide potential treatment of the above diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA234124-01A1
Application #
9818798
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Verma, Sharad Kumar
Project Start
2019-07-01
Project End
2024-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Ohio State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210