A novel orally available Syk/Src/Jak2 inhibitor, SKLB-850, showed potent anti-tumor activities in B cell lymphoma (BCL) models.
A novel orally available Syk/Src/Jak2 inhibitor, SKLB-850, showed potent anti-tumor activities in B cell lymphoma (BCL) models.
复制标题
一种新型口服 Syk/Src/Jak2 抑制剂 SKLB-850 在 B 细胞淋巴瘤 (BCL) 模型中显示出有效的抗肿瘤活性
DOI：
10.18632/oncotarget.22847
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发表时间：
2017-12-19
期刊：
影响因子：
--
通讯作者：
Yang SY
中科院分区：
文献类型：
--
作者：
Zhang N;Zhang G;Liu N;Lin W;Ji S;Zheng M;Chen K;Liang X;Li G;Ma Y;Zhu J;Niu T;Li LL;Li J;Wei YQ;Yang SY
B细胞淋巴瘤（BCL）是最常见的非霍奇金淋巴瘤（NHL）类型，约占美国所有癌症的4%。脾酪氨酸激酶（Syk）、Src和Janus激酶2 （JAK2）被认为是治疗BCL的潜在靶点。我们最近开发了一种多激酶抑制剂SKLB-850，它能有效抑制Syk、Src和JAK2。本研究旨在探讨SKLB-850在体外和体内的抗bcl活性及其作用机制。结果表明，SKLB-850能显著抑制BCL细胞增殖，诱导BCL细胞凋亡。可显著降低趋化因子CCL3、CCL4和CXCL12的分泌。口服SKLB-850显著抑制BCL异种移植模型（Ramos和HBL-1）的肿瘤生长，并呈剂量依赖性。肿瘤组织免疫组化结果显示，SKLB-850有效抑制Syk/ERK、Src/FAK和JAK2/Stat3通路的激活。综上所述，SKLB-850可能是一种有前景的治疗BCL的药物，值得进一步研究。
B cell lymphoma (BCL) is the most frequently diagnosed type of non-Hodgkin lymphoma (NHL), and accounts for about 4% of all cancers in the USA. Kinases spleen tyrosine kinase (Syk), Src, and Janus kinase 2 (JAK2) have been thought as potential targets for the treatment of BCL. We have recently developed a multikinase inhibitor, SKLB-850, which potently inhibits Syk, Src, and JAK2. The aim of this study is to investigate the anti-BCL activities and mechanisms of action of SKLB-850 both in vitro and in vivo. Our results showed that SKLB-850 significantly inhibited BCL cell proliferation, and induced apoptosis of BCL cells. It could considerably decrease the secretion of chemokines CCL3, CCL4, and CXCL12. Oral administration of SKLB-850 considerably suppressed the tumor growth in BCL xenograft models (Ramos and HBL-1) in a dose-dependent manner. Immunohistochemistry of tumor tissues showed that SKLB-850 efficiently inhibited the activation of Syk/ERK, Src/FAK and JAK2/Stat3 pathways. Collectively, SKLB-850 could be a promising agent for the treatment of BCL, hence deserving further study.
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