Discovery of a potential bladder cancer inhibitor CHNQD-01281 by regulating EGFRand promoting infiltration of cytotoxic T cells

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外文摘要：As one of the common malignancies that threaten human life,bladder cancer occurs frequently with a high mortality rate in the world,due to its invasion,recurrence and drug resistance.Natural products from marine microorganisms are becoming the hotspots in discovery of new candidate drug entities,especially in the area of cancer.Brefeldin A(BFA)is a natural Arf-GEFs inhibitor,but due to the low aqueous solubility,strong toxicity,and poor bioavailability,it is urgent to conduct structural optimization research.Herein,a new BFA pyridine acrylate derivative CHNQD-01281 with improved solubility was prepared and found to exert moderate to strong antiproliferative activity on a variety of human cancer cell lines.It was noteworthy that CHNQD-01281 was most sensitive to two bladder cancer cell lines T24 and J82(IC50=0.079 and 0.081 μmol/L)with high selectivity index(SI=14.68 and 14.32),suggesting a superior safety to BFA.In vivo studies revealed that CHNQD-01281 remarkably suppressed tumor growth in a T24 nude mice xenograft model(TGI=52.63％)and prolonged the survival time(ILS=68.16％)in an MB49 allogeneic mouse model via inducing infiltration of cytotoxic T cells.Further mechanism exploration indicated that CHNQD-01281 regulated both EGFR/PI3K/AKT and EGFR/ERK pathways and mediated the chemotactic effect of chemokines on immune effector cells.Overall,CHNQD-01281 may serve as a potential therapeutic agent for bladder cancer through multiple mechanisms.

外文关键词：

Bladder cancerMarine natural productsBrefeldin AEGFR/PI3K/AKTEGFR/ERKT-cell infiltration

作者：

Jian-Yu Liu、Yao-Yao Jiang、Peng-Jie Li、Bo Yao、Yi-Jing Song、Ji-Xiu Gao、Gulab Said、Yang Gao、Jun-Yu Lai、Chang-Lun Shao

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作者单位：

Key Laboratory of Marine Drugs,the Ministry of Education of China,School of Medicine and Pharmacy,Ocean University of China,Qingdao 266003,China

Department of Critical Care Medicine,the Affiliated Hospital of Qingdao University,Qingdao 266003,China

Department of Chemistry,Women University Swabi,Swabi 23430,Pakistan

Laoshan Laboratory,Qingdao 266237,China

Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education,College of Chemistry and Chemical Engineering,Hainan Normal University,Haikou 571158,China

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出版年：

2024

DOI：

10.1007/s42995-024-00246-w

海洋生命科学与技术(英文)

ISSN：

年,卷(期)：2024.6(3)