Research On Design, Synthesis And Bioactivity Of Selective B-RAF^V600E Inhibitor

Protein kinases could phosphorylate protein as known protein phosphatases. They play important roles in cellular signal transduction pathways and involved in the regulation of various physiological and pathological reactions. RAF kinases are the members of RAS/RAF/MEK/ERK signaling pathway(MAPK), their abnormal activation is an important factor of cancer development. B-RAF mutants were found in about 7%-9% human tumors. Over 90% of B-RAF mutation is B-RAFV600 E which a valine(V) was replaced with glutamic(E). Many classes of B-RAF small molecule inhibitors have been identified. Two selective inhibitors vemurafenib and dabrafenib have been approved by US FDA, and shown significant efficacy against metastatic and unresectable melanoma bearing B-RAFV600 E mutation in clinical. However, acquired resistance and side effect in clinic limits the therapeutic benefit of current used drugs. A new scaffold B- RAF inhibitor which could overcome drug resistance of tumor is desired.A series of N-(4-aminopyridin-2-yl)amide derivatives was designed as novel B-RafV600 E inhibitors by structural modifications based on a pan-Raf inhibitor TAK-632. We synthesized 20 compounds and revealed that most of the compounds displayed potent enzymatic activity against B-RAFV600 E, and excellent selectivity over B-RAFWT. The most promising 4l exhibited potent inhibitory activity with an IC50 value of 38 n M for B-RAFV600 E, and displayed antiproliferative activity against colo205 and HT29 with IC50 values of 136 and 94 n M, respectively. It also displayed good selectivity on both enzymatic and cellular assays over B-RAFWT. These inhibitors may serve as lead compounds for further developing novel B-RAFV600 E inhibitors as anticancer drugs.