The oncogenic mutations of BRAF which occur most frequently in V600E, leading to constitutive activation of the MAPK signaling pathway, are common in a variety of human cancers. Recently, drugs targeting RAF kinase have been approved as an effective treatment for human malignancies that rely on this target for their growth. Thus, suppressing RAF kinase activity is a clinically meaningful approach to treat cancer patients harboring RAF driven oncogene. In this study, a series of 2,5,8-trihydro-6,7-disubstituted-4-(3'-alkylsulfonamidoanilino)quinazoline was synthesized and evaluated for their RAF kinases inhibition activity. Several potent compounds displayed double-digit nanomolar IC50 values for RAF kinases including CRAF, BRAF, and BRAFV600E. Preliminary profiling of one of the most active compounds in a panel of protein kinases revealed its selectivity for RAF kinases. In cells, this compound exhibited selective cytotoxicity against cancer cells harboring BRAF V600E mutation and dose-dependent inhibition of phosphorylation of RAF downstream effectors MEK and ERK. Moreover, the compound was oral active in mice bearing A375 BRAFV600E‐mutant melanoma xenograft. Therefore, the novel quinazoline derivative proved to be active as RAF inhibitor.

Citation Format: Shih Chieh Yen, Shao-Zheng Peng, Hung-Jyun Huang, Ju-Ying Yang, Yen-Hsi Liu, Sian-Yi Ciou, Mann-Yan Kuo, Chu-Bin Liao. Novel 2,5,8-trihydro-6,7-disubstituted-4-(3'-alkylsulfonamidoanilino) quinazoline derivatives as RAF inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2809.