title: Design and synthesis of pyrrolo[3,2-d]pyrimidine human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors: exploration of novel back-pocket binders.
abstract: To develop novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) kinase inhibitors, we explored pyrrolo[3,2-d]pyrimidine derivatives bearing bicyclic fused rings designed to fit the back pocket of the HER2/EGFR proteins. Among them, the 1,2-benzisothiazole (42m) ring was selected as a suitable back pocket binder because of its potent HER2/EGFR binding and cell growth inhibitory (GI) activities and pseudoirreversibility (PI) profile as well as good bioavailability (BA). Ultimately, we arrived at our preclinical candidate 51m by optimization of the N-5 side chain to improve CYP inhibition and metabolic stability profiles without a loss of potency (HER2/EGFR inhibitory activity, IC(50), 0.98/2.5 nM; and GI activity BT-474 cells, GI(50), 2.0 nM). Reflecting the strong in vitro activities, 51m exhibited potent tumor regressive efficacy against both HER2- and EGFR-overexpressing tumor (4-1ST and CAL27) xenograft models in mice at oral doses of 50 mg/kg and 100 mg/kg.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited: 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Kawakita_Youichi@takeda.co.jp
authors.forename: Youichi
authors.initials: Y
authors.lastname: Kawakita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Banno
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ohashi
authors.forename: Toshiya
authors.initials: T
authors.lastname: Tamura
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yusa
authors.forename: Akiko
authors.initials: A
authors.lastname: Nakayama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miki
authors.forename: Hidehisa
authors.initials: H
authors.lastname: Iwata
authors.forename: Hidenori
authors.initials: H
authors.lastname: Kamiguchi
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Tanaka
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Habuka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sogabe
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Ohta
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Ishikawa
mesh_terms: D000818:Animals; D001682:Biological Availability; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D006885:Hydroxybutyrates / Q000138:chemical synthesis / Q000494:pharmacology*; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D006885:Hydroxybutyrates; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines; D011758:Pyrroles; D018719:Erb-b2 Receptor Tyrosine Kinases; C570404:N-(2-(4-((3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo(3,2-d)pyrimidin-5-yl)ethyl)-3-hydroxy-3-methylbutanamide