title: Structure-based design and synthesis of bicyclic fused-pyridines as MEK inhibitors.
abstract: The MAPK pathway is identified as one of the most important pathways involved in cell proliferation and differentiation. A key kinase in the pathway, the Mitogen-activated protein kinase kinase (MEK) is recognized as a promising target for antitumor drugs. Structure-based design and optimization of known MEK inhibitors resulted in identification of compound 10a as a potent non-ATP competitive MEK inhibitor in both in vitro and in vivo tests.
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd., Minhang District, Shanghai 200245, China. Electronic address: lvhj@shhrp.com.
authors.forename: Hejun
authors.initials: H
authors.lastname: Lu
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd., Minhang District, Shanghai 200245, China.
authors.forename: Wangyang
authors.initials: W
authors.lastname: Tu
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd., Minhang District, Shanghai 200245, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Fei
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd., Minhang District, Shanghai 200245, China.
authors.forename: Guoji
authors.initials: G
authors.lastname: Xu
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd., Minhang District, Shanghai 200245, China.
authors.forename: Qiyue
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd., Minhang District, Shanghai 200245, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd., Minhang District, Shanghai 200245, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Lin
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd., Minhang District, Shanghai 200245, China.
authors.forename: Jijun
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd., Minhang District, Shanghai 200245, China.
authors.forename: Junzhao
authors.initials: J
authors.lastname: Yin
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd., Minhang District, Shanghai 200245, China.
authors.forename: Aishen
authors.initials: A
authors.lastname: Gong
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd., Minhang District, Shanghai 200245, China.
authors.forename: Mimi
authors.initials: M
authors.lastname: Wan
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd., Minhang District, Shanghai 200245, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd., Minhang District, Shanghai 200245, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd., Minhang District, Shanghai 200245, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd., Minhang District, Shanghai 200245, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Shanghai Hengrui Pharmaceutical Co., Ltd, 279 Wenjing Rd., Minhang District, Shanghai 200245, China.
authors.forename: Piaoyang
authors.initials: P
authors.lastname: Sun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001643:Bridged Bicyclo Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Bicyclic; Cancer; Fused-pyridine; MEK; SBDD