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 ATP-dependent manner,as revealed by computational docking models.Cell-based assays showed that HCI-48 inhibited 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 cas-pase 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 PIM 1 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 FGFR1 kinases.This work provides a theoretical basis for the future application of HCI-48 in the treatment of clinical CRC.

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

Department of Pathophysiology,School of Basic Medical Sciences,Zhengzhou University,Zhengzhou 450001,China;China-US(Henan)Hormel Cancer Institute,Zhengzhou 450008,China;Translational Medical Center,the First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China;The Hormel Institute,University of Minnesota,Austin,MN 55912,USA;Department of Biomedicine,Health&Life Convergencen Science,BK21 Four,College of Pharmacy,Mokpo National University,Jeonnam 58554,Republic of Korea;The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention,Zhengzhou 450001,China;Department of General Surgery,the Affiliated Tumor Hospital of Zhengzhou University,Zhengzhou 450008,China;College of Korean Medicine,Dongshin University,Naju 58245,Republic of Korea

药学学报（英文版）

[1]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-.Novel dual inhibitor for targeting PIM1 and FGFR1 kinases inhibits colorectal cancer growth in vitro and patient-derived xenografts in vivo)[J].药学学报（英文版）,2022(11):4122-4137

Moloney,chalcones

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