title: A structure-guided optimization of pyrido[2,3-d]pyrimidin-7-ones as selective inhibitors of EGFRL858R/T790Mmutant with improved pharmacokinetic properties.
abstract: Structural optimization of pyrido[2,3-d]pyrimidin-7-ones was conducted to yield a series of new selective EGFRT790Minhibitors with improved pharmacokinetic properties. One of the most promising compound 9s potently suppressed EGFRL858R/T790Mkinase and inhibited the proliferation of H1975 cells with IC50values of 2.0 nM and 40 nM, respectively. The compound dose-dependently induced reduction of the phosphorylation of EGFR and downstream activation of ERK in NCIH1975 cells. It also exhibited moderate plasma exposure after oral administration and an oral bioavailability value of 16%. Compound 9s may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients.
authors.affiliation: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China; University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.affiliation: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China; University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China.
authors.forename: Minhao
authors.initials: M
authors.lastname: Huang
authors.affiliation: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China; University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China.
authors.forename: Tianfeng
authors.initials: T
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zu-Chong-Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors.forename: Linjiang
authors.initials: L
authors.lastname: Tong
authors.affiliation: Peking University Institute of Systems Biomedicine and Department of Biophysics, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Xiao-E
authors.initials: XE
authors.lastname: Yan
authors.affiliation: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Peking University Institute of Systems Biomedicine and Department of Biophysics, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Caihong
authors.initials: C
authors.lastname: Yun
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zu-Chong-Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China. Electronic address: hxie@simm.ac.cn.
authors.forename: Hua
authors.initials: H
authors.lastname: Xie
authors.affiliation: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China; School of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou 510632, China. Electronic address: ding_ke@gibh.ac.cn.
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
authors.affiliation: School of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou 510632, China. Electronic address: luxy2016@jnu.edu.cn.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Lu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D066246:ErbB Receptors
keywords: EGFR(T790M) mutant; Irreversible inhibitor; NSCLC; Pharmacokinetic property; Pyrido[2,3-d]pyrimidin-7-ones