Discovery of Novel Small-Molecule-Based Potential PD-L1/EGFR Dual Inhibitors with High Druggability for Glioblastoma Immunotherapy

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(10), С. 7995 - 8019

Опубликована: Май 13, 2024

Based on the close relationship between programmed death protein ligand 1 (PD-L1) and epidermal growth factor receptor (EGFR) in glioblastoma (GBM), we designed synthesized a series of small molecules as potential dual inhibitors EGFR PD-L1. Among them, compound EP26 exhibited highest inhibitory activity against (IC50 = 37.5 nM) PD-1/PD-L1 interaction 1.77 μM). In addition, displayed superior vitro antiproliferative activities immunomodulatory effects by promoting U87MG cell U87MG/Jurkat coculture model. Furthermore, possessed favorable pharmacokinetic properties (F 22%) inhibited tumor (TGI 92.0%) GBM mouse model more effectively than Gefitinib (77.2%) NP19 (82.8%). Moreover, increased CD4+ cells CD8+ microenvironment. Collectively, these results suggest that represents first small-molecule-based PD-L1/EGFR inhibitor deserving further investigation an immunomodulating agent for cancer treatment.

Язык: Английский

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A Nanoimmunoactivator Induces Endoplasmic Reticulum Stress and Alleviates the Immunosuppression for Synergistic Cancer Immunotherapy

Advanced Functional Materials, Год журнала: 2025, Номер unknown

Опубликована: Янв. 16, 2025

Abstract Cancer immunotherapy has transformed the landscape of cancer treatment. However, low immunogenicity and immunosuppressive tumor microenvironment (TME) often limit efficacy immunotherapy. Activating immune responses while alleviating negative feedback regulation offers a promising strategy to enhance effectiveness Herein, this work proposes novel nanoparticle‐based activator (nanoIA), which can induce immunogenic cell death (ICD) cells deliver small‐molecule immunomodulators further antitumor responses. NanoIA features unique surface structure that enables it ICD by targeting retaining in endoplasmic reticulum cells. Additionally, nanoIA be loaded with various drugs released response stimuli from TME. This distinct capability initiate amplify study employs two immunomodulators, JQ1 NLG919, as examples for demonstration. NanoIA/JQ1 nanoIA/NLG919 demonstrated significant inhibiting growth, prolonging survival tumor‐bearing mice, preventing recurrence metastasis. These results confirm nanoIA's ability activate memory. provides new insights into development nanoparticles actively participate regulation.

Язык: Английский

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Research Progress in Bifunctional small molecules for cancer immunotherapy

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер 286, С. 117289 - 117289

Опубликована: Янв. 19, 2025

Язык: Английский

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A new method for constructing pyrido[3',2':4,5]imidazo[1,2-<em>b</em>]pyridazine system and preparation of its derivatives

Mendeleev Communications, Год журнала: 2025, Номер 35(1), С. 24 - 26

Опубликована: Янв. 1, 2025

Язык: Английский

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A bioengineered antibody conjugate reshape dendritic cell viability for immune-tolerance modulation

Chemical Engineering Journal, Год журнала: 2025, Номер unknown, С. 160431 - 160431

Опубликована: Фев. 1, 2025

Язык: Английский

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