Small Molecule Degraders of Protein Tyrosine Phosphatase 1B and T-Cell Protein Tyrosine Phosphatase for Cancer Immunotherapy.
Immunotherapy
PROTAC Degrader
PTP1B
TC-PTP
Journal
Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Titre abrégé: Angew Chem Int Ed Engl
Pays: Germany
ID NLM: 0370543
Informations de publication
Date de publication:
22 05 2023
22 05 2023
Historique:
received:
15
03
2023
pmc-release:
22
05
2024
medline:
15
5
2023
pubmed:
28
3
2023
entrez:
27
3
2023
Statut:
ppublish
Résumé
Protein tyrosine phosphatase 1B (PTP1B) and T-cell protein tyrosine phosphatase (TC-PTP) play non-redundant negative regulatory roles in T-cell activation, tumor antigen presentation, insulin and leptin signaling, and are potential targets for several therapeutic applications. Here, we report the development of a highly potent and selective small molecule degrader DU-14 for both PTP1B and TC-PTP. DU-14 mediated PTP1B and TC-PTP degradation requires both target protein(s) and VHL E3 ligase engagement and is also ubiquitination- and proteasome-dependent. DU-14 enhances IFN-γ induced JAK1/2-STAT1 pathway activation and promotes MHC-I expression in tumor cells. DU-14 also activates CD8
Identifiants
pubmed: 36973833
doi: 10.1002/anie.202303818
pmc: PMC10196813
mid: NIHMS1896621
doi:
Substances chimiques
Protein Tyrosine Phosphatase, Non-Receptor Type 2
EC 3.1.3.48
Protein Tyrosine Phosphatase, Non-Receptor Type 1
EC 3.1.3.48
4-O-(sulfamoyl)-N-tetradecanoyltyramine
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202303818Subventions
Organisme : NCI NIH HHS
ID : R01 CA069202
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG064250
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA023168
Pays : United States
Informations de copyright
© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.
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