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

  • J Enzyme Inhib Med Chem. 2023 Dec;38(1):2230388. doi: 10.1080/14756366.2023.2230388.
Hua Zhang  1  2 ,  Shi-Jia Zhou  1  2 ,  Chen-Feng Shen  1  2 ,  Yong-Nan Zhou  1  2 ,  Cai-Yun Wu  1  2 ,  Meng-Yu Zhu  1  2 ,  Qi-Meng Yu  1  2 ,  Annoor Awadasseid  1  2  3 ,  Yan-Ling Wu  4 ,  Wen Zhang  1  2  5
Affiliations
  • 1. Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, China.
  • 2. Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou, China.
  • 3. Moganshan Institute, Zhejiang University of Technology, Deqing, China.
  • 4. Lab of Molecular Immunology, Virus Inspection Department, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China.
  • 5. Zhejiang Jieyuan Pharmaceutical Technology Co., LTD, Hangzhou, China.
PMID: 37439326 DOI: 10.1080/14756366.2023.2230388
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.

Keywords
Biphenyl derivative; GSK-3β; PD-L1; apoptosis; non-immune pathway.
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