title: Identification of a selective inhibitor of transforming growth factor β-activated kinase 1 by biosensor-based screening of focused libraries.
abstract: Transforming growth factor-β activated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase family, plays an essential role in mediating signals from various pro-inflammatory cytokines and therefore may be a good target for developing anti-inflammation agents. Herein, we report our efforts to identify TAK1 inhibitors with a good selectivity profile with which to initiate medicinal chemistry. Instead of resorting to a high-throughput screening campaign, we performed biosensor-based biophysical screening for a limited number of compounds by taking advantage of existing knowledge on kinase inhibitors. Rather than focusing on one specific inhibition mode, we searched for three different types, Type I (ATP-competitive, DFG-in), Type II (DFG-out), and Type III binders (non-ATP competitive) in parallel, and succeeded in identifying candidates in all three categories efficiently and rapidly. Finally, the biosensor-based binding kinetics for the active and inactive forms of TAK1 were measured to prioritize the Type I and Type II inhibitors. The effort resulted in the identification of a new TAK1-selective Type I compound with a thienopyrimidine scaffold that served as a good starting point for medicinal chemistry.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan. Electronic address: miuratka@chugai-pharm.co.jp.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Miura
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Matsuo
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Terushige
authors.initials: T
authors.lastname: Muraoka
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ide
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Morikami
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kamikawa
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Nishihara
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kashiwagi
mesh_terms: D015374:Biosensing Techniques; D006801:Humans; D007700:Kinetics; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020349:Surface Plasmon Resonance; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020930:MAP Kinase Kinase Kinases; D047428:Protein Kinase Inhibitors; D000099151:MAP Kinase Kinase Kinase 7
keywords: Biophysical screening; Chemogenomic approach; Selective Type I inhibitor; TAK1