title: Design and synthesis of N-(4-aminopyridin-2-yl)amides as B-Raf(V600E) inhibitors.
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.
authors.affiliation: College of Pharmacy, Jilin University, Changchun 130021, China.
authors.forename: Xiaokai
authors.initials: X
authors.lastname: Li
authors.affiliation: College of Pharmacy, Jilin University, Changchun 130021, China.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Li
authors.initials: L
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Donglin
authors.initials: D
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Cheng
authors.affiliation: College of Pharmacy, Jilin University, Changchun 130021, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhou
authors.affiliation: College of Pharmacy, Jilin University, Changchun 130021, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
authors.affiliation: 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.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Lu
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D019073:HT29 Cells; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf
keywords: B-Raf(V600E) inhibitor; N-(4-Aminopyridin-2-yl)amides; Selective; Structural modification