Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Characterization of KRC-108 as a TrkA Kinase Inhibitor with Anti-Tumor Effects

  • Lee, Hyo Jeong (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University) ;
  • Moon, Yeongyu (Gyeongnam Biohealth Research Center, Gyeongnam Branch Institute, Korea Institute of Toxicology) ;
  • Choi, Jungil (Gyeongnam Biohealth Research Center, Gyeongnam Branch Institute, Korea Institute of Toxicology) ;
  • Heo, Jeong Doo (Gyeongnam Biohealth Research Center, Gyeongnam Branch Institute, Korea Institute of Toxicology) ;
  • Kim, Sekwang (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University) ;
  • Nallapaneni, Hari Krishna (College of Pharmacy, Kangwon National University) ;
  • Chin, Young-Won (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • Lee, Jongkook (College of Pharmacy, Kangwon National University) ;
  • Han, Sun-Young (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University)
  • Received : 2021.12.28
  • Accepted : 2022.02.09
  • Published : 2022.07.01
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Abstract

Tropomyosin receptor kinase A (TrkA) protein is a receptor tyrosine kinase encoded by the NTRK1 gene. TrkA signaling mediates the proliferation, differentiation, and survival of neurons and other cells following stimulation by its ligand, the nerve growth factor. Chromosomal rearrangements of the NTRK1 gene result in the generation of TrkA fusion protein, which is known to cause deregulation of TrkA signaling. Targeting TrkA activity represents a promising strategy for the treatment of cancers that harbor the TrkA fusion protein. In this study, we evaluated the TrkA-inhibitory activity of the benzoxazole compound KRC-108. KRC-108 inhibited TrkA activity in an in vitro kinase assay, and suppressed the growth of KM12C colon cancer cells harboring an NTRK1 gene fusion. KRC-108 treatment induced cell cycle arrest, apoptotic cell death, and autophagy. KRC-108 suppressed the phosphorylation of downstream signaling molecules of TrkA, including Akt, phospholipase Cγ, and ERK1/2. Furthermore, KRC-108 exhibited antitumor activity in vivo in a KM12C cell xenograft model. These results indicate that KRC-108 may be a promising therapeutic agent for Trk fusion-positive cancers.

Keywords

Acknowledgement

This research was funded by the National Research Foundation, Government of Korea, grant number 2021R1A2C1007790 (S-Y.H.) and 2021R1A2C2010431 (J.L.).

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