An Aurora kinase inhibitor BPR6K471 inhibits tumor growth and reduces the cancer stem cell-like properties of small cell lung cancer

Small cell lung cancer (SCLC) is one the most aggressive tumors with poor survival rate. SCLC patients often present with metastasis at time of diagnosis, excluding surgery as a treatment option. While patients show high response rate to standard chemotherapy such as cisplatin/etoposide, they soon develop drug resistance and disease progression. Therefore, new therapeutic strategies are urgently needed for SCLC. Several characteristics of SCLC such as aggressiveness and drug resistance could attribute to the existence of a cancer stem cell (CSC) subpopulation in SCLC. The SCLC cell line NCI-H446 has been shown to present high degree of stemness and express stem cell markers including CD133, OCT4, MYC and Nestin. Here we develop a pyrimidine-based small molecule BPR6K471 which potently inhibits Aurora kinase activities in enzymatic- and cell- based assays. BPR6K471 efficiently (IC50 = 66 nM) inhibits proliferation of NCI-H446, and reduces the expression of stem-cell markers. In addition, intravenous injection of BPR6K471 inhibits >90 % progression of NCI-H446 in a mouse xenograft model. These results suggest that targeting Aurora kinases may be a potential therapeutic strategy to combat the CSC subpopulation in SCLC. Citation Format: Chun-Ping Chang, Yi-Yu Ke, Wen-Hsing Lin, Dai-Hui Jhuo, Wan-Ping Wang, Chia-Hua Tsai, Yen-Ting Chen, Yu-Jie Su, Ming-Chun Hung, Zhong-Wei Wu, Po-Chu Kuo, Teng-Kuang Yeh, Ching-Ping Chen, Jen-Shin Song, Chiun-Tong Chen, Chuan Shih, Ya-Hui Chi. An Aurora kinase inhibitor BPR6K471 inhibits tumor growth and reduces the cancer stem cell-like properties of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3851.