Design and synthesis of N-(4-aminopyridin-2-yl)amides as B-Raf(V600E) inhibitors

  • Bioorg Med Chem Lett. 2016 Jun 15;26(12):2760-2763. doi: 10.1016/j.bmcl.2016.04.076.
Xiaokai Li  1 ,  Jiayi Shen  1 ,  Li Tan  2 ,  Zhang Zhang  3 ,  Donglin Gao  2 ,  Jinfeng Luo  3 ,  Huimin Cheng  3 ,  Xiaoping Zhou  1 ,  Jie Ma  1 ,  Ke Ding  4 ,  Xiaoyun Lu  5
Affiliations
  • 1. College of Pharmacy, Jilin University, Changchun 130021, China.
  • 2. State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China; University of Chinese Academy of Sciences, #19 Yuquan Road, Beijing 100049, China.
  • 3. State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China.
  • 4. State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China. Electronic address: [email protected].
  • 5. School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China; State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China. Electronic address: [email protected].
PMID: 27155899 DOI: 10.1016/j.bmcl.2016.04.076
Abstract

B-Raf(V600E) was an effective target for the treatment of human cancers. Based on a pan-Raf inhibitor TAK-632, a series of N-(4-aminopyridin-2-yl)amide derivatives were designed as novel B-Raf(V600E) inhibitors. Detailed structure-activity studies of the compounds revealed that most of the compounds displayed potent enzymatic activity against B-Raf(V600E), and good selectivity over B-Raf(WT). One of the most promising compound 4l exhibited potent inhibitory activity with an IC50 value of 38nM for B-Raf(V600E), and displayed antiproliferative activities against colo205 and HT29 cells with IC50 values of 0.136 and 0.094μM, respectively. It also displayed good selectivity on both enzymatic and cellular assays over B-Raf(WT). These inhibitors may serve as lead compounds for further developing novel B-Raf(V600E) inhibitors as Anticancer drugs.

Keywords
B-Raf(V600E) inhibitor; N-(4-Aminopyridin-2-yl)amides; Selective; Structural modification.