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; Kangdong Liu; Zhi Li; Kyle Vaughn Laster; Zigang Dong; Mee-Hyun Lee

doi:10.1016/j.apsb.2022.07.005

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

Acta Pharm Sin B. 2022 Nov;12(11):4122-4137. doi: 10.1016/j.apsb.2022.07.005. Epub 2022 Jul 15.

Authors

Fanxiang Yin^{1

2

3}, Ran Zhao^{1

2}, Dhilli Rao Gorja², Xiaorong Fu^{1

2}, Ning Lu^{1

2}, Hai Huang², Beibei Xu^{1

2}, Hanyong Chen⁴, Jung-Hyun Shim⁵, Kangdong Liu^{1

2

6}, Zhi Li⁷, Kyle Vaughn Laster², Zigang Dong^{1

2

4}, Mee-Hyun Lee^{1

2

8}

Affiliations

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 Zhengzhou 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.

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.

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