Design and optimization of orally spleen tyrosine kinase (SYK) inhibitors for treatment of solid tumor.,Bioorganic Chemistry

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Design and optimization of orally spleen tyrosine kinase (SYK) inhibitors for treatment of solid tumor.
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2019-12-24 , DOI: 10.1016/j.bioorg.2019.103547
Cheng Wang ₁ , Xin Wang ₁ , Yao Li ₂ , Tianqi Wang ₂ , Zhi Huang ₂ , Zhongxiang Qin ₂ , Shengyong Yang ₃ , Rong Xiang ₄ , Yan Fan ₁

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As the aim to discover orally SYK inhibitors for solid tumor treatment, a series of novel derivatives based on imidazo[1,2-a]pyrazine scaffold were designed, synthesized and evaluated. Structure-activity relationship study of both enzymatic and cellular assays led to the identification of compound 12f. The novel SYK inhibitor 12f showed potent antitumor activity against solid tumors with favorable drug-like properties of lipophilicity and solubility. 12f could induce cell apoptosis of ovarian and lung cancer cell lines. In SKOV3 xenograft mouse model, oral administration of 12f led to significant tumour regression without obvious toxicity. 12f improved the limited response of traditional SYK inhibitors in solid tumors in vitro and in vivo. Taken together, this compound may act as a promising lead compound for further development of new SYK inhibitors for solid tumor therapy.

中文翻译：

口服脾酪氨酸激酶（SYK）抑制剂的设计和优化，用于治疗实体瘤。

为了发现口服SYK抑制剂治疗实体瘤的目的，设计，合成和评估了一系列基于咪唑并[1,2-a]吡嗪骨架的新型衍生物。酶和细胞分析的结构-活性关系研究导致了化合物12f的鉴定。新型SYK抑制剂12f对实体瘤表现出有效的抗肿瘤活性，并具有亲脂性和溶解性等良好的类药物性质。12f可以诱导卵巢癌细胞和肺癌细胞凋亡。在SKOV3异种移植小鼠模型中，口服12f导致明显的肿瘤消退而没有明显的毒性。12f在体外和体内改善了传统SYK抑制剂在实体瘤中的有限反应。在一起

更新日期：2019-12-25

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