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Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers, leading to ~30,000 deaths each year in the United States. 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. BPR6K609S0 is a novel Aurora kinase inhibitor which has been designed to inhibit the kinase activity of Aurora A, and induces proteasome-mediated degradation of MYC. The BPR6K609S0 active molecule provokes cell apoptosis and inhibits proliferation of several SCLC cell lines with IC50 < 100 nM. Oral administration of BPR6K609 induces >60 % tumor regression in a NCI-H446 xenograft mouse model. In addition, BPR6K609 further reduces tumor progression in NCI-H446 xenograft mice pre-treated with LY3295668, an Aurora A-selective inhibitor which is currently under clinical investigation. These results support the clinical potential of BRP6K609S0 for the treatment of SCLC. Citation Format: Ya-Hui Chi, Chun-Ping Chang, Yi-Yu Ke, Wen-Hsing Lin, Wan-Ping Wang, Chia-Hua Tsai, Yen-Ting Chen, Yu-Jie Su, Ming-Chun Hung, Zhong-Wei Wu, Mine-Hsine Wu, Teng-Kuang Yeh, Ching-Ping Chen, Jen-Shin Song, Chiung-Tong Chen, Chuan Shih. BPR6K609: An Aurora kinase inhibitor targeting small cell lung cancer with MYC amplification [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1937.

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.