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

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

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: ding_ke@gibh.ac.cn.
  • 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: lu_xiaoyun@gibh.ac.cn.
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.

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