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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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 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 FGFR1 kinases. This work provides a theoretical basis for the future application of HCI-48 in the treatment of clinical CRC.

Original languageEnglish (US)
Pages (from-to)4122-4137
Number of pages16
JournalActa Pharmaceutica Sinica B
Volume12
Issue number11
DOIs
StatePublished - Nov 2022

Bibliographical note

Funding Information:
This work was supported by grant funding from the National Natural Science Foundation of China ( 81972839 , 82002620 and 82073075 ), and the Scientific and Technological Project in Henan Province and Henan Provincial Government (Nos. 212102310882 , and 222102310104 , China). We wish to thank Dr. Xiang Li, Ran Yang, Sen Yang, and Fangfang Liu in the China-US (Henan) Hormel Cancer Institute, Zhengzhou, China for supporting materials and experiments, and Dr. Jaeki Min in Induced Proximity Platform (IPP) Amgen, USA for discussing the HCI-48 compound.

Funding Information:
This work was supported by grant funding from the National Natural Science Foundation of China (81972839, 82002620 and 82073075), and the Scientific and Technological Project in Henan Province and Henan Provincial Government (Nos. 212102310882, and 222102310104, China). We wish to thank Dr. Xiang Li, Ran Yang, Sen Yang, and Fangfang Liu in the China-US (Henan) Hormel Cancer Institute, Zhengzhou, China for supporting materials and experiments, and Dr. Jaeki Min in Induced Proximity Platform (IPP) Amgen, USA for discussing the HCI-48 compound.

Publisher Copyright:
© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences

Keywords

  • Colorectal cancer
  • FGFR1
  • HCI-48
  • Kinase activity
  • PIM1
  • Patient-derived xenograft model
  • Small molecule compound of chalcone
  • Targeted therapy

PubMed: MeSH publication types

  • Journal Article

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