PD-L1 dimerisation induced by biphenyl derivatives mediates anti-breast cancer activity via the non-immune PD-L1–AKT–mTOR/Bcl2 pathway

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 (IC₅₀ = 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.

Graphical Abstract

HIGHLIGHTS

• 10 novel biphenyl derivatives were designed and synthesised.

• 12j–4 can cause the apoptosis of MDA-MB-231 cells with an IC₅₀ value of 2.68 ± 0.27 μM in the absence of immune cells.

• 12j–4 prevents the phosphorylation of AKT by binding to cytoplasmic PD-L1 to induce apoptosis through non-immune pathways.

Keywords:

• Biphenyl derivative
• PD-L1
• GSK-3β
• non-immune pathway
• apoptosis

Author contributions

The work was done through the contributions of all the authors. All authors have approved the final version of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by grants from the National Natural Science Foundation of China [Nos. 21877101, 22177105], the Zhejiang Leading Innovation and Entrepreneurship Team [2018R01015] and the Zhejiang Provincial Key Discipline of Chemical Biology.