title: Knowledge-based identification of the ERK2/STAT3 signal pathway as a therapeutic target for type 2 diabetes and drug discovery.
abstract: Many existing agents for diabetes therapy are unable to restore or maintain normal glucose homeostasis or prevent the eventual emergence of hyperglycemia-related complication. Therefore, agents based on novel mechanisms are sought to complement and extend the current therapeutic approaches. Based on the initial paper research, we focused on active STAT3 as an attractive pharmacological target for type 2 diabetes. The subsequent text mining with a unique query to identify suppressors but not activators of STAT3 revealed the ERK2/STAT3 pathway as a novel diabetes target. The description of ERK2 inhibitors as diabetes target had not been found in our text mining research at present. The mechanism-based peptide inhibitor for ERK2 was identified using the knowledge of the KIM sequence, which has an important role in the recognition of cognate kinases, phosphatases, scaffold proteins, and substrates. The peptide inhibitor was confirmed to exert effects in vitro and in vivo. The peptide inhibitor conferred a significant decrease in HOMA-IR levels on Day 28 compared with that in the vehicle group. Besides lowering the fasting blood glucose level, the peptide inhibitor also attenuated the blood glucose increment in the fed state, as compared with the vehicle group.
authors.affiliation: Graduate School of Science, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan. kinotk@b.s.osakafu-u.ac.jp
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Kentaro
authors.initials: K
authors.lastname: Doi
authors.forename: Hajime
authors.initials: H
authors.lastname: Sugiyama
authors.forename: Shuhei
authors.initials: S
authors.lastname: Kinoshita
authors.forename: Mutsuyo
authors.initials: M
authors.lastname: Wada
authors.forename: Shuji
authors.initials: S
authors.lastname: Naruto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tomonaga
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D001786:Blood Glucose; D010455:Peptides; D050796:STAT3 Transcription Factor; D019950:Mitogen-Activated Protein Kinase 1