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  3. Advancing Cancer Immunotherapy through Engineering New PD-L1 Degraders: A Comprehensive Study from Small Molecules to PD-L1-Specific Peptide-Drug Conjugates

Advancing Cancer Immunotherapy through Engineering New PD-L1 Degraders: A Comprehensive Study from Small Molecules to PD-L1-Specific Peptide-Drug Conjugates

  • J Med Chem. 2024 Oct 18. doi: 10.1021/acs.jmedchem.4c01652.
Zekun Zeng 1,  Zhiwei Yang 2,  Chenghao Li 1,  Shujing Liu 1,  Wei Wei 3,  Ye Zhou 1,  Simeng Wang 1,  Mengjun Sui 1,  Mengdan Li 4,  Shumei Lin 5,  Yangyang Cheng 1,  Peng Hou 1
Affiliations

Affiliations

  • 1 International Joint Research Center for Tumor Precision Medicine of Shaanxi Province and Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P. R. China.
  • 2 MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
  • 3 Department of Ultrasound Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P. R. China.
  • 4 Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P. R. China.
  • 5 Department of Infectious Disease Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P. R. China.
PMID: 39420825 DOI: 10.1021/acs.jmedchem.4c01652
Abstract

Despite the considerable achievements of Antibodies targeting PD-1/PD-L1 in Cancer Immunotherapy, limitations in antitumor immune response and pharmacokinetics hinder their clinical adoption. Small molecules toward PD-L1 degradation signifies an innovative avenue to modulate PD-1/PD-L1 axis. Herein, we unveil a comprehensive engineering involving the development of new PD-L1 degraders based on the berberine (BBR) and palmatine (PMT) bioactive frameworks and explore their translational potential for Cancer Immunotherapy using a peptide-drug conjugate strategy. Chemical modifications at the O-9 position of PMT dramatically enhance the PD-L1 degradation capacity. Further conjugation of PMT degraders with an anti-PD-L1 peptide featuring disulfide linkers enables efficient GSH-specific prodrug activation, yielding synergistic immunotherapeutic benefits through both external PD-L1 blockade and internal PD-L1 degradation mechanisms. This work elucidates the compelling charm of the discovery and application of PD-L1 degraders, offering solutions to the challenges in advancing Cancer Immunotherapy in widespread clinics.

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