Novel dual inhibitor for targeting PIM1 and FGFR1 kinases inhibits colorectal cancer growth in vitro and patient-derived xenografts in vivo  

作　　者：Fanxiang Yin Ran Zhao Dhilli Rao Gorja Xiaorong Fu Ning Lu Hai Huang Beibei Xu Hanyong Chen Jung-Hyun Shim Kangdong Liu Zhi Li Kyle Vaughn Laster Zigang Dong Mee-Hyun Lee 

机构地区：[1]Department of Pathophysiology,School of Basic Medical Sciences,Zhengzhou University,Zhengzhou 450001,China [2]China-US(Henan)Hormel Cancer Institute,Zhengzhou 450008,China [3]Translational Medical Center,the First Affiliated Hospital of Zheng zhou University,Zhengzhou 450052,China [4]The Hormel Institute,University of Minnesota,Austin,MN 55912,USA [5]Department of Biomedicine,Health&Life Convergencen Science,BK21 Four,College of Pharmacy Mokpo National University,Jeonnam 58554,Republic of Korea [6]The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention,Zhengzhou 450001,China [7]Department of General Surgery,the Affiliated Tumor Hospital of Zhengzhou University,Zhengzhou 450008,China [8]College of Korean Medicine,Dongshin University,Naju 58245,Republic of Korea

出　　处：《Acta Pharmaceutica Sinica B》2022年第11期4122-4137,共16页药学学报（英文版）

基　　金：supported by grant funding from the National Natural Science Foundation of China(81972839,82002620 and 82073075);the Scientific and Technological Project in Henan Province and Henan Provincial Government(Nos.212102310882,and 222102310104,China).

摘　　要：Colorectal cancer(CRC) is the second most common cause of cancer-related death in the world. The pro-viral integration site for Moloney murine leukemia virus 1(PIM1) is a proto-oncogene and belongs to the serine/threonine kinase family, which are involved in cell proliferation, migration,and apoptosis. Fibroblast growth factor receptor 1(FGFR1) is a tyrosine kinase that has been implicated in cell proliferation, differentiation and migration. Small molecule HCI-48 is a derivative of chalcone, a class of compounds known to possess anti-tumor, anti-inflammatory and antibacterial effects. However,the underlying mechanism of chalcones against colorectal cancer remains unclear. This study reports that HCI-48 mainly targets PIM1 and FGFR1 kinases, thereby eliciting antitumor effects on colorectal cancer growth in vitro and in vivo. HCI-48 inhibited the activity of both PIM1 and FGFR1 kinases in an ATPdependent manner, as revealed by computational docking models. Cell-based assays showed that HCI-48inhibited cell proliferation in CRC cells(HCT-15, DLD1, HCT-116 and SW620), and induced cell cycle arrest in the G2/M phase through modulation of cyclin A2. HCI-48 also induced cellular apoptosis, as evidenced by an increase in the expression of apoptosis biomarkers such as cleaved PARP, cleaved caspase 3 and cleaved caspase 7. Moreover, HCI-48 attenuated the activation of downstream components of the PIM1 and FGFR1 signaling pathways. Using patient-derived xenograft(PDX) murine tumor models,we found that treatment with HCI-48 diminished the PDX tumor growth of implanted CRC tissue expressing high protein levels of PIM1 and FGFR1. This study suggests that the inhibitory effect of HCI-48 on colorectal tumor growth is mainly mediated through the dual-targeting of PIM1 and FGFR1kinases. This work provides a theoretical basis for the future application of HCI-48 in the treatment of clinical CRC.

关 键 词：PIM1 FGFR1 Colorectal cancer HCI-48 Targeted therapy Small moleculecompound ofchalcone Patient-derived xenograft model ATPKinase activity 

分 类 号：R965[医药卫生—药理学]