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

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

SUBMITTER: Zeng Z 

PROVIDER: S-EPMC11571110 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature