Novel quinazoline derivative as RAF Inhibitor

2^nd International Conference on PHARMACEUTICAL CHEMISTRY

October 02-04, 2017 Barcelona, Spain

Shih-Chieh Yen, Chu-Bin Liao, Hung-Jyun Huang, Ju-Ying Yang, Yen-Hsi Liu, Sian-Yi Ciou, Mann-Yan Kuo, and Shao-Zheng Peng

Development Center for Biotechnology, Institute of Pharmaceutics, Taiwan

Posters & Accepted Abstracts: Med Chem (Los Angeles)

Abstract :

The oncogenic mutations of BRAF, 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 in cancer patients harboring RAF driven oncogene. In this study, a series of quinazoline derivative 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, the compound exhibited selective cytotoxicity against cancer cells harboring BRAF V600E mutation and dose-dependent inhibition of the phosphorylation of RAF downstream effectors MEK and ERK. Moreover, the compound was oral active in mice bearing A375 BRAFV600Eâ�?mutant melanoma xenograft. Therefore, the novel quinazoline derivative proved to be active as RAF inhibitor.

Biography :

Shih-Chieh Yen has completed his PhD at the age of 30 years from Tsing-Hua University and postdoctoral studies from National Health Research Institutes, Institute of Biotechnology and Pharmaceutical Research. I am the research fellow of Development Center for Biotechnology, Institute of Pharmaceutics, an organic synthesis chemist service organization.