The screening of combinatorial peptide libraries for targeting key molecules or protein-protein interactions in the NF-κB pathway
File(s)
Accepted version
Accepted version
Author(s)
Type
Journal Article
Abstract
Peptides are emerging as an increasingly dependable class of therapeutics in the treatment of cancer and metabolic and cardiovascular diseases, which are all areas of high interest to the pharmaceutical industry. The global market for peptide therapeutics was valued at about 25 billion USD in 2018 and is estimated to reach 57.2 billion USD by the end of 2027. Here, we describe a method for the screening and deconvolution of combinatorial peptide libraries to discover compounds that target discrete signaling components of the NF-κB pathway. Recently, we used this approach to specifically disrupt the interaction between the JNK-activating kinase, MKK7, and the NF-κB-regulated antiapoptotic factor, GADD45β, in multiple myeloma (MM). We showed that the GADD45β/MKK7 complex is a functionally critical survival module downstream of NF-κB in MM cells and as such provides an attractive therapeutic target to selectively inhibit NF-κB antiapoptotic signaling in cancer cells. By integrating the library screening and deconvolution methods described here with a rational chemical optimization strategy, we developed the first-in-class GADD45β/MKK7 inhibitor, DTP3 (a D-tripeptide), which is now being trialed in MM and diffuse large B-cell lymphoma (DLBCL) patients. The same drug discovery approach may be generally applied to therapeutically target other key components of the NF-κB pathway in cancers beyond MM and DLBCL, as well as in non-malignant NF-κB-driven diseases.
Date Issued
2021-07-09
Date Acceptance
2021-01-01
Citation
Methods in Molecular Biology, 2021, 2366, pp.343-356
ISSN
1064-3745
Publisher
Humana Press
Start Page
343
End Page
356
Journal / Book Title
Methods in Molecular Biology
Volume
2366
Copyright Statement
© Springer Science+Business Media, LLC, part of Springer Nature 2021. The final publication is available at Springer via https://link.springer.com/protocol/10.1007/978-1-0716-1669-7_21
Sponsor
Medical Research Council (MRC)
Bloodwise
Imperial College Healthcare NHS Trust- BRC Funding
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/34236649
Grant Number
MR/L005069/1
15003
RDF01
Subjects
Apoptosis
Cancer
Combinatorial chemistry
Drug discovery
GADD45β
MKK7
NF-κB
Peptides
Targeted therapy
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2021-07-09