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

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tyrosine
Non-Small Cell Lung Carcinoma
DNA Repair
Protein-Tyrosine Kinases
lungs
inhibitors
DNA Damage
Receptor Protein-Tyrosine Kinases
DNA
Repair
deoxyribonucleic acid
cancer
Cells
damage
Administrative data processing
ribose
adenosine diphosphate
genes
Genes
phenotype

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

Cite this

Antitumor activity of a novel tyrosine kinase inhibitor AIU2001 due to abrogation of the DNA damage repair in non-small cell lung cancer cells. / Ryu, Hwani; Choi, Hyun Kyung; Kim, Hyo Jeong; Kim, Ah Young; Song, Jie Young; Hwang, Sang Gu; Kim, Jae Sung; Kim, Da Un; Kim, Eun Ho; Kim, Joon; Ahn, Jiyeon.

In: International journal of molecular sciences, Vol. 20, No. 19, 4728, 01.10.2019.

Research output: Contribution to journalArticle

Ryu, Hwani ; Choi, Hyun Kyung ; Kim, Hyo Jeong ; Kim, Ah Young ; Song, Jie Young ; Hwang, Sang Gu ; Kim, Jae Sung ; Kim, Da Un ; Kim, Eun Ho ; Kim, Joon ; Ahn, Jiyeon. / Antitumor activity of a novel tyrosine kinase inhibitor AIU2001 due to abrogation of the DNA damage repair in non-small cell lung cancer cells. In: International journal of molecular sciences. 2019 ; Vol. 20, No. 19.
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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.",
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AU - Ryu, Hwani

AU - Choi, Hyun Kyung

AU - Kim, Hyo Jeong

AU - Kim, Ah Young

AU - Song, Jie Young

AU - Hwang, Sang Gu

AU - Kim, Jae Sung

AU - Kim, Da Un

AU - Kim, Eun Ho

AU - Kim, Joon

AU - Ahn, Jiyeon

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AB - 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.

KW - Apoptosis

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KW - FLT3 inhibitor

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KW - PARP-1 inhibitor

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