title: Design and synthesis of novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors bearing a pyrrolo[3,2-d]pyrimidine scaffold.
abstract: Dual inhibitors of human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the receptors' ATP binding site. Among the prepared compounds, 34e showed potent HER2 and EGFR (HER1) inhibitory activities as well as tumor growth inhibitory activity. The X-ray cocrystal structures of 34e with both HER2 and EGFR demonstrated that 34e interacts with the expected residues in their respective ATP pockets. Furthermore, reflecting its good oral bioavailability, 34e exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report 34e (TAK-285) as a promising candidate for clinical development as a novel HER2/EGFR dual kinase inhibitor.
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Ishikawa_Tomoyasu@takeda.co.jp
authors: Tomoyasu
authors: T
authors: Ishikawa
authors: Masaki
authors: M
authors: Seto
authors: Hiroshi
authors: H
authors: Banno
authors: Youichi
authors: Y
authors: Kawakita
authors: Mami
authors: M
authors: Oorui
authors: Takahiko
authors: T
authors: Taniguchi
authors: Yoshikazu
authors: Y
authors: Ohta
authors: Toshiya
authors: T
authors: Tamura
authors: Akiko
authors: A
authors: Nakayama
authors: Hiroshi
authors: H
authors: Miki
authors: Hidenori
authors: H
authors: Kamiguchi
authors: Toshimasa
authors: T
authors: Tanaka
authors: Noriyuki
authors: N
authors: Habuka
authors: Satoshi
authors: S
authors: Sogabe
authors: Jason
authors: J
authors: Yano
authors: Kathleen
authors: K
authors: Aertgeerts
authors: Keiji
authors: K
authors: Kamiyama
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D001682:Biological Availability; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D006885:Hydroxybutyrates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D011487:Protein Conformation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D066246:ErbB Receptors; D006885:Hydroxybutyrates; 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; C508053:ERBB2 protein, human