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

• Published in: International journal of molecular sciences Vol. 20; no. 19; p. 4728
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 24.09.2019; MDPI
• Subjects: Angiogenesis; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Apoptosis - drug effects; c-Kit protein; Cancer therapies; Carcinoma, Non-Small-Cell Lung; Cell cycle; cell cycle arrest; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell proliferation; Chemical compounds; Class III RTK; Deoxyribonucleic acid; Disease Models, Animal; DNA; DNA Damage; DNA damage repair; DNA repair; DNA Repair - drug effects; Dose-Response Relationship, Drug; Drug Synergism; Drugs; Enzyme inhibitors; FLT3 inhibitor; Gene expression; Genes; Growth factors; Humans; Hydrogen bonds; Kinases; Lung cancer; Lung Neoplasms; Mice; Molecular Structure; Non-small cell lung carcinoma; NSCLC; PARP-1 inhibitor; Pharmacology; Phase transitions; Phenotypes; Phosphorylation; Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase receptors; Proteins; Radiation therapy; Repair; Ribose; Stat5 protein; Structure-Activity Relationship; Tumors; Tyrosine; Xenograft Model Antitumor Assays; DNA damage repair; NSCLC; Class III RTK; PARP-1 inhibitor; apoptosis; cell cycle arrest; FLT3 inhibitor
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20194728

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 was downregulated by AIU2001 treatment and knockdown of 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.