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PD-L1 dimerisation induced by biphenyl derivatives mediates anti-breast cancer activity via the non-immune PD-L1-AKT-mTOR/Bcl2 pathway.
- Source :
-
Journal of enzyme inhibition and medicinal chemistry [J Enzyme Inhib Med Chem] 2023 Dec; Vol. 38 (1), pp. 2230388. - Publication Year :
- 2023
-
Abstract
- Recent studies on biphenyl-containing compounds, a type of PD-1/PD-L1 blocker which binds to PD-L1 and induces dimerisation, have focussed on its immune function. Herein, 10 novel biphenyl derivatives were designed and synthesised. The results of the CCK-8 showed that compounds have different anti-tumour activities for tumour cells in the absence of T cells. Particularly, 12j-4 can significantly induce the apoptosis of MDA-MB-231 cells (IC <subscript>50</subscript> = 2.68 ± 0.27 μM). In further studies, 12j-4 has been shown to prevent the phosphorylation of AKT by binding to cytoplasmic PD-L1, which induces apoptosis in MDA-MB-231 cells through non-immune pathways. The inhibition of AKT phosphorylation restores the activity of GSK-3β, ultimately resulting in the degradation of PD-L1. Besides, in vivo study indicated that 12j-4 repressed tumour growth in nude mice. As these biphenyls exert their anti-tumour effects mainly through non-immune pathways, they are worthy of further study as PD-L1 inhibitors.
Details
- Language :
- English
- ISSN :
- 1475-6374
- Volume :
- 38
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of enzyme inhibition and medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 37439326
- Full Text :
- https://doi.org/10.1080/14756366.2023.2230388