2. Academic Validation
  3. Improving tumor sensitivity by the introduction of an ester chain to triaryl derivatives targeting PD-1/PD-L1

Improving tumor sensitivity by the introduction of an ester chain to triaryl derivatives targeting PD-1/PD-L1

  • Eur J Med Chem. 2024 May 5:271:116433. doi: 10.1016/j.ejmech.2024.116433.
Yonglei Zhang 1,  Fucheng Yin 1,  Zhongwen Luo 1,  Shang Li 1,  Xinxin Li 1,  Siyuan Wan 1,  Yifan Chen 1,  Lingyi Kong 2,  Xiaobing Wang 3
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: cpu_lykong@126.com.
  • 3 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: xbwang@cpu.edu.cn.
PMID: 38678826 DOI: 10.1016/j.ejmech.2024.116433
Abstract

PD-1/PD-L1 pathway blockade is a promising immunotherapy for the treatment of Cancer. In this manuscript, a series of triaryl compounds containing ester chains were designed and synthesized based on the pharmacophore studies of the lead BMS-1. After several SAR iterations, 22 showed the best biochemical activity binding to hPD-L1 with an IC50 of 1.21 nM in HTRF assay, and a KD value of 5.068 nM in SPR analysis. Cell-based experiments showed that 22 effectively promoted A549 cell death by restoring T-cell immune function. 22 showed significant in vivo antitumor activity in a 4T1 mouse model without obvious toxicity, with a TGI rate of 67.8 % (20 mg/kg, ip). Immunohistochemistry data indicated that 22 activates the immune activity in tumors. These results suggest that 22 is a promising compound for further development of PD-1/PD-L1 inhibitor for Cancer therapy.

Keywords

Immunotherapy; PD-1/PD-L1; Pharmacophore; SAR; T-cell.

Figures
Products