Antitumor Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to Abrogation of the DNA Damage Repair in Non-Small Cell Lung Cancer Cells.
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.
['Ryu|Hwani|H|', 'Choi|Hyun-Kyung|HK|', 'Kim|Hyo Jeong|HJ|', 'Kim|Ah-Young|AY|', 'Song|Jie-Young|JY|0000-0002-5769-3886', 'Hwang|Sang-Gu|SG|', 'Kim|Jae-Sung|JS|', 'Kim|Da-Un|DU|', 'Kim|Eun-Ho|EH|0000-0002-6476-163X', 'Kim|Joon|J|', 'Ahn|Jiyeon|J|']
D000818:Animals D000970:Antineoplastic Agents D017209:Apoptosis D002289:Carcinoma, Non-Small-Cell Lung D059447:Cell Cycle Checkpoints D045744:Cell Line, Tumor D004249:DNA Damage D004260:DNA Repair D004195:Disease Models, Animal D004305:Dose-Response Relationship, Drug D004357:Drug Synergism D006801:Humans D008175:Lung Neoplasms D051379:Mice D015394:Molecular Structure D000071137:Poly (ADP-Ribose) Polymerase-1 D000067856:Poly(ADP-ribose) Polymerase Inhibitors D047428:Protein Kinase Inhibitors D013329:Structure-Activity Relationship D023041:Xenograft Model Antitumor Assays
DNA damage repair Class III RTK NSCLC cell cycle arrest FLT3 inhibitor PARP-1 inhibitor apoptosis