title: TAE226, a Bis-Anilino Pyrimidine Compound, Inhibits the EGFR-Mutant Kinase Including T790M Mutant to Show Anti-Tumor Effect on EGFR-Mutant Non-Small Cell Lung Cancer Cells.
abstract: TAE226, a bis-anilino pyrimidine compound, has been developed as an inhibitor of focal adhesion kinase (FAK) and insulin-like growth factor-I receptor (IGF-IR). In this study, we investigated the effect of TAE226 on non-small-cell lung cancer (NSCLC), especially focusing on the EGFR mutational status. TAE226 was more effective against cells with mutant EGFR, including the T790M mutant, than against cells with wild-type one. TAE226 preferentially inhibited phospho-EGFR and its downstream signaling mediators in the cells with mutant EGFR than in those with wild-type one. Phosphorylation of FAK and IGF-IR was not inhibited at the concentration at which the proliferation of EGFR-mutant cells was inhibited. Results of the in vitro binding assay indicated significant differences in the affinity for TAE226 between the wild-type and L858R (or delE746_A750) mutant, and the reduced affinity of ATP to the L858R (or delE746_A750) mutant resulted in good responsiveness of the L858R (or delE746_A750) mutant cells to TAE226. Of interest, the L858R/T790M or delE746_A750/T790M mutant enhanced the binding affinity for TAE226 compared with the L858R or delE746_A750 mutant, resulting in the effectiveness of TAE226 against T790M mutant cells despite the T790M mutation restoring the ATP affinity for the mutant EGFR close to that for the wild-type. TAE226 also showed higher affinity of about 15-fold for the L858R/T790M mutant than for the wild-type one by kinetic interaction analysis. The anti-tumor effect against EGFR-mutant tumors including T790M mutation was confirmed in mouse models without any significant toxicity. In summary, we showed that TAE226 inhibited the activation of mutant EGFR and exhibited anti-proliferative activity against NSCLCs carrying EGFR mutations, including T790M mutation.
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Otani
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of General Surgery, Kawasaki Medical School, Okayama 700-8505, Japan.
authors.forename: Munenori
authors.initials: M
authors.lastname: Takaoka
authors.affiliation: Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sakaguchi
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Soh
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Jida
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Kubo
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Asano
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Tsukuda
authors.affiliation: Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kiura
authors.affiliation: Musculoskeletal Disease Area, Novartis Institutes for BioMedical Research Basel, Novartis Pharma AG, CH-4056, Basel, Switzerland.
authors.forename: Shinji
authors.initials: S
authors.lastname: Hatakeyama
authors.affiliation: Department of Medical Science Liaison, Department of Oncology Development/Medical Affairs, Novartis Pharma K.K., Tokyo 106-0031, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kawahara
authors.affiliation: Department of General Surgery, Kawasaki Medical School, Okayama 700-8505, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Naomoto
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Miyoshi
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Toyooka
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D009154:Mutation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C524632:TAE226; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D000077156:Gefitinib