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Synthesis and Biological Evaluation of 3-Amino-4,4-Dimethyl Lithocholic Acid Derivatives as Novel, Selective, and Cellularly Active Allosteric SHP1 Activators.
- Source :
-
Molecules (Basel, Switzerland) [Molecules] 2023 Mar 08; Vol. 28 (6). Date of Electronic Publication: 2023 Mar 08. - Publication Year :
- 2023
-
Abstract
- Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1), a non-receptor member of the protein tyrosine phosphatase (PTP) family, negatively regulates several signaling pathways that are responsible for pathological cell processes in cancers. In this study, we report a series of 3-amino-4,4-dimethyl lithocholic acid derivatives as SHP1 activators. The most potent compounds, 5az-ba , showed low micromolar activating effects (EC <subscript>50</subscript> : 1.54-2.10 μM) for SHP1, with 7.63-8.79-fold maximum activation and significant selectivity over the closest homologue Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) (>32-fold). 5az-ba showed potent anti-tumor effects with IC <subscript>50</subscript> values of 1.65-5.51 μM against leukemia and lung cancer cells. A new allosteric mechanism of SHP1 activation, whereby small molecules bind to a central allosteric pocket and stabilize the active conformation of SHP1, was proposed. The activation mechanism was consistent with the structure-activity relationship (SAR) data. This study demonstrates that 3-amino-4,4-dimethyl lithocholic acid derivatives can be selective SHP1 activators with potent cellular efficacy.
Details
- Language :
- English
- ISSN :
- 1420-3049
- Volume :
- 28
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Molecules (Basel, Switzerland)
- Publication Type :
- Academic Journal
- Accession number :
- 36985458
- Full Text :
- https://doi.org/10.3390/molecules28062488