title: Design, synthesis, and biological evaluation of 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl derivatives as new irreversible epidermal growth factor receptor inhibitors with improved pharmacokinetic properties.
abstract: Structural optimization of a series of 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl compounds, potential new irreversible EGFR inhibitors, was performed to improve pharmacokinetic properties of the compounds. This led to compound 2v with improved aqueous solubility and good pharmacokinetic properties which at the nanomolar level potently inhibits gefitinib-resistant EGFR(L858R/T790M) kinase and displays strong antiproliferative activity against H1975 nonsmall cell lung cancer cells. The new inhibitor also shows promising antitumor efficacy in a murine EGFR(L858R/T790M)-driven H1975 xenograft model without effect on body weight. These studies provide new lead compounds for further development of drugs for treatment of gefitinib-resistant nonsmall cell lung cancer patients.
authors.affiliation: Institute of Chemical Biology , Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , #190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Shilin
authors.initials: S
authors.lastname: Xu
authors.forename: Tianfeng
authors.initials: T
authors.lastname: Xu
authors.forename: Lianwen
authors.initials: L
authors.lastname: Zhang
authors.forename: Zhang
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Luo
authors.forename: Yingxue
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Lu
authors.forename: Zhengchao
authors.initials: Z
authors.lastname: Tu
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Ren
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
mesh_terms: D000818:Animals; 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; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D023041:Xenograft Model Antitumor Assays
chemical_list: C587007:1-(1-acryloylpyrrolidin-3-yl)-7-(3-methyl-4-(4-methylpiperazin-1-yl)phenylamino)-3-phenyl-3,4-dihydropyrimido(4,5-d)pyrimidin-2(1H)-one; D000970:Antineoplastic Agents; D006574:Heterocyclic Compounds, 2-Ring; D011743:Pyrimidines; D066246:ErbB Receptors