Erlotinib-Gold(I) Complex Induces Leukemia Cell DC Differentiation and Remodels the Immunosuppressive Microenvironment

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2024-12-10 DOI:10.1021/acs.jmedchem.4c01354

Xiaoxuan Yu, Yanyu Zhou, Xiaoyan Ma, Wan Zhang, Fuwei Li, Fengyu Jiang, Yawen Wang, Qin Zhang, Wukun Liu

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Abstract

Inducing differentiation of leukemia cells into dendritic cells (DC) is pivotal to reshaping the immunosuppressive microenvironment. Here, we report the synthesis of EG2, an erlotinib-gold(I) complex, which directly prompts the differentiation of acute myeloid leukemia (AML) cells into DCs. A patient-derived xenograft (PDX) model underscores the potent anti-AML activity of EG2. Mechanistic studies reveal that EG2 initiates the activation of the PPARγ/RXRα heterodimer by targeting thioredoxin reductase (TrxR) and the epidermal growth factor receptor (EGFR). This activation culminates in the expression of genes associated with the differentiation of the AML cells into DCs as well as pyroptosis, effectively reshaping the immune microenvironment both in vitro and in vivo. Overall, this study marks the first instance of a gold-based small molecule inducing the direct differentiation of tumor cells into immune cells and offers a promising and innovative strategy for the design of AML immunotherapies.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.