Peptide-tiling screens of cancer drivers reveal oncogenic protein domains and associated peptide inhibitors.
cancer drivers
inhibitors
peptides
protein-protein interactions
Journal
Cell systems
ISSN: 2405-4720
Titre abrégé: Cell Syst
Pays: United States
ID NLM: 101656080
Informations de publication
Date de publication:
21 07 2021
21 07 2021
Historique:
received:
29
05
2020
revised:
09
02
2021
accepted:
30
03
2021
pubmed:
30
5
2021
medline:
7
4
2022
entrez:
29
5
2021
Statut:
ppublish
Résumé
Gene fragments derived from structural domains mediating physical interactions can modulate biological functions. Utilizing this, we developed lentiviral overexpression libraries of peptides comprehensively tiling high-confidence cancer driver genes. Toward inhibiting cancer growth, we assayed ~66,000 peptides, tiling 65 cancer drivers and 579 mutant alleles. Pooled fitness screens in two breast cancer cell lines revealed peptides, which selectively reduced cellular proliferation, implicating oncogenic protein domains important for cell fitness. Coupling of cell-penetrating motifs to these peptides enabled drug-like function, with peptides derived from EGFR and RAF1 inhibiting cell growth at IC50s of 27-63 μM. We anticipate that this peptide-tiling (PepTile) approach will enable rapid de novo mapping of bioactive protein domains and associated interfering peptides.
Identifiants
pubmed: 34051140
pii: S2405-4712(21)00157-5
doi: 10.1016/j.cels.2021.05.002
pmc: PMC8298269
mid: NIHMS1700087
pii:
doi:
Substances chimiques
Peptides
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
716-732.e7Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM123313
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL105373
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA222826
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG009285
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA209891
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors have filed a patent based on this work. P.M. is a scientific co-founder of Shape Therapeutics, Boundless Biosciences, Seven Therapeutics, Navega Therapeutics, and Engine Biosciences. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of-interest policies.
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