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Discovery of Novel HDAC3 Inhibitors with PD-L1 Downregulating/Degrading and Antitumor Immune Effects.
Sun, Zhiqiang; Xu, Chenglong; Cheng, Jinmei; Yang, Zichao; Liu, Ting; Deng, Bulian; Zhang, Xuewen; Peng, Xiaopeng; Chen, Jianjun.
Afiliación
  • Sun Z; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
  • Xu C; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
  • Cheng J; Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
  • Yang Z; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
  • Liu T; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
  • Deng B; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
  • Zhang X; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
  • Peng X; Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Jiangxi Province Key Laboratory of Biomaterials and Biofabrication for Tissue Engineering, School of Pharmacy, Gannan Medical University, Ganzhou 314000, China.
  • Chen J; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
J Med Chem ; 67(15): 13067-13088, 2024 Aug 08.
Article en En | MEDLINE | ID: mdl-39031090
ABSTRACT
Targeting the programmed cell death-1/ligand 1 (PD-1/PD-L1) pathway is one of the most promising cancer treatment strategies. Studies have shown that HDAC inhibitors can enhance the antitumor immune response by modulating the expression of PD-L1. Herein, we designed and synthesized a series of novel hydrazide-based small molecule HDAC inhibitors; among them, compound HQ-30 showed selective HDAC3 inhibition (IC50 = 89 nM) and remarkable PD-L1-degrading activity (DC50 = 5.7 µM, Dmax = 80% at 10 µM). Further studies revealed that HQ-30 induced the degradation of PD-L1 by regulating cathepsin B (CTSB) in the lysosomes. Further, HQ-30 could enhance the infiltration of CD3+ CD4+ helper T and CD3+ CD8+ cytotoxic T cells in tumors, thus activating the tumor immune microenvironment. Moreover, HQ-30 possessed a benign toxicity profile (LD50 > 1000 mg/kg) and favorable pharmacokinetic properties (F = 57%). Taken together, HQ-30 is worthy of further investigation as a small molecule-based epigenetic modulator of tumor immunotherapy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores de Histona Desacetilasas / Antígeno B7-H1 / Histona Desacetilasas / Antineoplásicos Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores de Histona Desacetilasas / Antígeno B7-H1 / Histona Desacetilasas / Antineoplásicos Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos