Targeting the actin nucleation promoting factor WASp provides a therapeutic approach for hematopoietic malignancies.
Actins
/ metabolism
Animals
Antineoplastic Agents
/ metabolism
Cell Movement
/ drug effects
Cell Proliferation
/ drug effects
Cytoskeletal Proteins
/ metabolism
Hematologic Neoplasms
/ drug therapy
Humans
Integrins
/ metabolism
Intracellular Signaling Peptides and Proteins
/ metabolism
Mice
Neoplasm Invasiveness
Protein Binding
/ drug effects
Small Molecule Libraries
/ metabolism
Ubiquitination
/ drug effects
Wiskott-Aldrich Syndrome Protein
/ metabolism
Xenograft Model Antitumor Assays
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
22 09 2021
22 09 2021
Historique:
received:
16
03
2020
accepted:
03
09
2021
entrez:
23
9
2021
pubmed:
24
9
2021
medline:
21
10
2021
Statut:
epublish
Résumé
Cancer cells depend on actin cytoskeleton rearrangement to carry out hallmark malignant functions including activation, proliferation, migration and invasiveness. Wiskott-Aldrich Syndrome protein (WASp) is an actin nucleation-promoting factor and is a key regulator of actin polymerization in hematopoietic cells. The involvement of WASp in malignancies is incompletely understood. Since WASp is exclusively expressed in hematopoietic cells, we performed in silico screening to identify small molecule compounds (SMCs) that bind WASp and promote its degradation. We describe here one such identified molecule; this WASp-targeting SMC inhibits key WASp-dependent actin processes in several types of hematopoietic malignancies in vitro and in vivo without affecting naïve healthy cells. This small molecule demonstrates limited toxicity and immunogenic effects, and thus, might serve as an effective strategy to treat specific hematopoietic malignancies in a safe and precisely targeted manner.
Identifiants
pubmed: 34552085
doi: 10.1038/s41467-021-25842-7
pii: 10.1038/s41467-021-25842-7
pmc: PMC8458504
doi:
Substances chimiques
Actins
0
Antineoplastic Agents
0
Cytoskeletal Proteins
0
Integrins
0
Intracellular Signaling Peptides and Proteins
0
Small Molecule Libraries
0
WAS protein, human
0
WIPF1 protein, human
0
Wiskott-Aldrich Syndrome Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5581Informations de copyright
© 2021. The Author(s).
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