바로가기  >

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.

Author information

Ryu H1,2, Choi HK3, Kim HJ4, Kim AY5, Song JY6, Hwang SG7, Kim JS8, Kim DU9, Kim EH10, Kim J11, Ahn J12.
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.