Please use this identifier to cite or link to this item: https://doi.org/10.18632/oncotarget.8572
Title: Avoiding drug resistance through extended drug target interfaces: A case for stapled peptides
Authors: Wei, S.J
Chee, S
Yurlova, L
Lane, D 
Verma, C 
Brown, C
Ghadessy, F
Keywords: nutlin
peptide inhibitor
protein inhibitor
protein MDM2
protein p53
unclassified drug
antineoplastic agent
MDM2 protein, human
peptide
protein binding
protein MDM2
protein p53
TP53 protein, human
animal cell
Article
BHK cell line
binding affinity
controlled study
drug protein binding
drug resistance
fibroblast
fluorescence polarization
immunoprecipitation
in vitro study
molecular model
mouse
neoplasm
nonhuman
phenotype
point mutation
protein binding
protein expression
protein function
protein purification
Western blotting
wild type
animal
antagonists and inhibitors
binding site
cell line
chemistry
drug design
drug effects
gene expression regulation
genetics
genotype
human
metabolism
molecular mimicry
neoplasm
pathology
signal transduction
structure activity relation
Animals
Antineoplastic Agents
Binding Sites
Cell Line
Drug Design
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
Genotype
Humans
Mice
Models, Molecular
Molecular Mimicry
Neoplasms
Peptides
Phenotype
Point Mutation
Protein Binding
Proto-Oncogene Proteins c-mdm2
Signal Transduction
Structure-Activity Relationship
Tumor Suppressor Protein p53
Issue Date: 2016
Citation: Wei, S.J, Chee, S, Yurlova, L, Lane, D, Verma, C, Brown, C, Ghadessy, F (2016). Avoiding drug resistance through extended drug target interfaces: A case for stapled peptides. Oncotarget 7 (22) : 32232-32246. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.8572
Rights: Attribution 4.0 International
Abstract: Cancer drugs often fail due to the emergence of clinical resistance. This can manifest through mutations in target proteins that selectively exclude drug binding whilst retaining aberrant function. A priori knowledge of resistance-inducing mutations is therefore important for both drug design and clinical surveillance. Stapled peptides represent a novel class of antagonists capable of inhibiting therapeutically relevant protein-protein interactions. Here, we address the important question of potential resistance to stapled peptide inhibitors. HDM2 is the critical negative regulator of p53, and is often overexpressed in cancers that retain wild-type p53 function. Interrogation of a large collection of randomly mutated HDM2 proteins failed to identify point mutations that could selectively abrogate binding by a stapled peptide inhibitor (PM2). In contrast, the same interrogation methodology has previously uncovered point mutations that selectively inhibit binding by Nutlin, the prototypical small molecule inhibitor of HDM2. Our results demonstrate both the high level of structural p53 mimicry employed by PM2 to engage HDM2, and the potential resilience of stapled peptide antagonists to mutations in target proteins. This inherent feature could reduce clinical resistance should this class of drugs enter the clinic.
Source Title: Oncotarget
URI: https://scholarbank.nus.edu.sg/handle/10635/179927
ISSN: 19492553
DOI: 10.18632/oncotarget.8572
Rights: Attribution 4.0 International
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