Antitumor activity of a novel tyrosine kinase inhibitor AIU2001 due to abrogation of the DNA damage repair in non-small cell lung cancer cells

Hwani Ryu, Hyun Kyung Choi, Hyo Jeong Kim, Ah Young Kim, Jie Young Song, Sang Gu Hwang, Jae Sung Kim, Da Un Kim, Eun Ho Kim, Joon Kim, Jiyeon Ahn

Research output: Contribution to journalArticle

Abstract

Class III receptor tyrosine kinase (RTK) inhibitors targeting mainly FLT3 or c-KIT have not been well studied in lung cancer. To identify a small molecule potentially targeting class III RTK, we synthesized novel small molecule compounds and identified 5-(4-bromophenyl)-N-(naphthalen-1-yl) oxazol-2-amine (AIU2001) as a novel class III RKT inhibitor. In an in vitro kinase profiling assay, AIU2001 inhibited the activities of FLT3, mutated FLT3, FLT4, and c-KIT of class III RTK, and the proliferation of NSCLC cells in vitro and in vivo. AIU2001 induced DNA damage, reactive oxygen species (ROS) generation, and cell cycle arrest in the G2/M phase. Furthermore, AIU2001 suppressed the DNA damage repair genes, resulting in the ‘BRCAness’/‘DNA-PKness’ phenotype. The mRNA expression level of STAT5 was downregulated by AIU2001 treatment and knockdown of STAT5 inhibited theDNArepair genes. Our results show that compared to either drug alone, the combination of AIU2001 with a poly (ADP-ribose) polymerase (PARP) inhibitor olaparib or irradiation showed synergistic efficacy in H1299 and A549 cells. Hence, our findings demonstrate that AIU2001 is a candidate therapeutic agent for NSCLC and combination therapies with AIU2001 and a PARP inhibitor or radiotherapy may be used to increase the therapeutic efficacy of AIU2001 due to inhibition of DNA damage repair.

Original languageEnglish
Article number4728
JournalInternational journal of molecular sciences
Volume20
Issue number19
DOIs
Publication statusPublished - 2019 Oct 1

Keywords

  • Apoptosis
  • Cell cycle arrest
  • Class III RTK
  • DNA damage repair
  • FLT3 inhibitor
  • NSCLC
  • PARP-1 inhibitor

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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