A novel orally available Syk/Src/Jak2 inhibitor, SKLB-850, showed potent anti-tumor activities in B cell lymphoma (BCL) models

作者:Zhang, Nannan; Zhang, Guo; Liu, Ning; Lin, Wanting; Ji, Sen; Zheng, Mingwu; Chen, Kai; Liang, Xiao; Li, Guobo; Ma, Yu; Zhu, Jun; Niu, Ting; Li, Lin-Li; Li, Jiong; Wei, Yu-Quan; Yang, Sheng-Yong*
来源:Oncotarget, 2017, 8(67): 111495-111507.
DOI:10.18632/oncotarget.22847

摘要

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.