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

Zekun Zeng,

Zhiwei Yang, Chenghao Li

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(21), P. 19216 - 19233

Published: Oct. 18, 2024

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

Language: Английский

In situ peptide assembly for cell membrane rewiring in tumor therapy DOI
Yu Ma, Qiaochu Jiang, Xiaoyang Liu

et al.

Journal of Controlled Release, Journal Year: 2025, Volume and Issue: unknown, P. 113637 - 113637

Published: March 1, 2025

Language: Английский

Citations

0
A CXCR4-targeted immunomodulatory nanomedicine for photodynamic amplified immune checkpoint blockade therapy against breast cancer DOI
Yibin Liu,

Xiayun Chen,

Wei Zhang

et al.

Acta Biomaterialia, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

Citations

0
Discovery of Dual PD-L1/HDAC3 Inhibitors for Tumor Immunotherapy DOI
Zhijie Wang,

Haiqi He,

Xiaotong Liao

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 15, 2025

Targeting programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway has been considered as one of the most promising strategies for tumor immunotherapy. However, single-target PD-1/PD-L1 inhibitors frequently exhibit limited efficacy, highlighting urgent need new therapies. Herein, a series dual PD-L1/HDAC3 were developed through pharmacophore fusion strategy first time. Among them, compound PH3 was identified inhibitor, with potent inhibitory activity (IC50 = 89.4 nM) and selective HDAC3 107 nM). Moreover, exhibited superior in vitro antitumor activities immune activation effects. Additionally, showed dose-dependent efficacy B16-F10 melanoma mouse model without obvious toxicity. Furthermore, increased infiltration CD3+CD8+ CD3+CD4+ cells microenvironment. Collectively, represented novel inhibitor deserving further investigation immunotherapy agent.

Language: Английский

Citations

0
Targeted protein degradation with small molecules for cancer immunotherapy DOI Creative Commons
Zichao Yang,

Jianwei Xu,

Xixiang Yang

et al.

Asian Journal of Pharmaceutical Sciences, Journal Year: 2025, Volume and Issue: unknown, P. 101058 - 101058

Published: April 1, 2025

Language: Английский

Citations

0
Fatty acid synthase (FASN) is a tumor-cell-intrinsic metabolic checkpoint restricting T-cell immunity DOI Creative Commons
Elisabet Cuyàs,

Stefano Pedarra,

Sara Verdura

et al.

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: Sept. 30, 2024

Language: Английский

Citations

2
Small Molecule Inhibitors Targeting PD-L1, CTLA4, VISTA, TIM-3, and LAG3 for Cancer Immunotherapy (2020-2024) DOI
Binbin Cheng,

Jiaoli Lv,

Yao Xiao

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 283, P. 117141 - 117141

Published: Dec. 5, 2024

Language: Английский

Citations

2
Intrinsic PD‐L1 Degradation Induced by a Novel Self‐Assembling Hexapeptide for Enhanced Cancer Immunotherapy DOI Creative Commons
Hongxia Zhang, Ming Ji, Yamei Wang

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 12(2)

Published: Nov. 12, 2024

Abstract Programmed death‐ligand 1 (PD‐L1) is a critical immune checkpoint protein that facilitates tumor evasion. While antibody‐based PD‐1/PD‐L1 inhibitors have shown promise, their limitations necessitate the development of alternative therapeutic strategies. This work addresses these challenges by developing hexapeptide, KFM (Lys‐Phe‐Met‐Phe‐Met‐Lys), capable both directly downregulating PD‐L1 and self‐assembling into ROS‐responsive supramolecular hydrogel. dual functionality allows Gel to function as localized drug delivery system inhibitor. Loading hydrogel with mitoxantrone (MTX) metformin (MET) further enhances effect combining chemotherapy downregulation. In vitro in vivo studies demonstrate significant growth inhibition, increased CD8+ T cell infiltration, reduced intratumoral expression following peritumoral administration. Mechanistically, promotes degradation via ubiquitin‐dependent pathway. “carrier‐free” expands role hydrogels beyond passive carriers active immunotherapeutic agents, offering promising new strategy for cancer therapy.

Language: Английский

Citations

1
Discovery of Small Molecules for Autophagy-lysosome Degradation of Immune Checkpoint Proteins DOI
Kaizhen Wang,

Zhihao Qi,

Jiazheng Guo

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 280, P. 116958 - 116958

Published: Oct. 16, 2024

Language: Английский

Citations

0
Advancing Cancer Immunotherapy through Engineering New PD-L1 Degraders: A Comprehensive Study from Small Molecules to PD-L1-Specific Peptide–Drug Conjugates DOI Creative Commons

Zekun Zeng,

Zhiwei Yang, Chenghao Li

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(21), P. 19216 - 19233

Published: Oct. 18, 2024

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

Language: Английский

Citations

0