2. Academic Validation
  3. Antitumor Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to Abrogation of the DNA Damage Repair in Non-Small Cell Lung Cancer Cells

Antitumor Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to Abrogation of the DNA Damage Repair in Non-Small Cell Lung Cancer Cells

  • Int J Mol Sci. 2019 Sep 24;20(19):4728. doi: 10.3390/ijms20194728.
Hwani Ryu 1 2,  Hyun-Kyung Choi 3,  Hyo Jeong Kim 4,  Ah-Young Kim 5,  Jie-Young Song 6,  Sang-Gu Hwang 7,  Jae-Sung Kim 8,  Da-Un Kim 9,  Eun-Ho Kim 10,  Joon Kim 11,  Jiyeon Ahn 12
Affiliations

Affiliations

  • 1 Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences (KIRAMS), Seoul 01812, Korea. hwanya85@kirams.re.kr.
  • 2 Department of Biology, Korea University, Seoul 02841, Korea. hwanya85@kirams.re.kr.
  • 3 Department of Medicinal Chemistry, Jungwon University, Goesan 28024, Korea. hkchoi45@jwu.ac.kr.
  • 4 Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences (KIRAMS), Seoul 01812, Korea. hjkim@kirams.re.kr.
  • 5 Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences (KIRAMS), Seoul 01812, Korea. tenderlady0513@gmail.com.
  • 6 Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences (KIRAMS), Seoul 01812, Korea. immu@kirams.re.kr.
  • 7 Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences (KIRAMS), Seoul 01812, Korea. sgh63@kirams.re.kr.
  • 8 Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences (KIRAMS), Seoul 01812, Korea. jaesung@kirams.re.kr.
  • 9 Department of Medicinal Chemistry, Jungwon University, Goesan 28024, Korea. kdw-101010@naver.com.
  • 10 Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences (KIRAMS), Seoul 01812, Korea. eh140149@kirams.re.kr.
  • 11 Department of Biology, Korea University, Seoul 02841, Korea. joonkim@korea.ac.kr.
  • 12 Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences (KIRAMS), Seoul 01812, Korea. ahnjy@kirams.re.kr.
PMID: 31554189 DOI: 10.3390/ijms20194728
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 the DNA repair 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.

Keywords

Class III RTK; DNA damage repair; FLT3 inhibitor; NSCLC; PARP-1 inhibitor; apoptosis; cell cycle arrest.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-112802
    99.69%, c-Kit Inhibitor