title: The ASK1-specific inhibitors K811 and K812 prolong survival in a mouse model of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure. To develop effective treatments for this devastating disease, an appropriate strategy for targeting the molecule responsible for the pathogenesis of ALS is needed. We previously reported that mutant SOD1 protein causes motor neuron death through activation of ASK1, a mitogen-activated protein kinase kinase kinase. Additionally, we recently developed K811 and K812, which are selective inhibitors for ASK1. Here, we report the effect of K811 and K812 in a mouse model of ALS (SOD1(G93A) transgenic mice). Oral administration of K811 or K812 significantly extended the life span of SOD1(G93A) transgenic mice (1.06 and 1.08% improvement in survival). Moreover, ASK1 activation observed in the lumbar spinal cord of mice at the disease progression stage was markedly decreased in the K811- and K812-treated groups. In parallel, immunohistochemical analysis revealed that K811 and K812 treatment inhibited glial activation in the lumbar spinal cord of SOD1(G93A) transgenic mice. These results reinforce the importance of ASK1 as a therapeutic target for ALS treatment.
authors.affiliation: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Fujisawa
authors.affiliation: Tokyo Research Park, R&D Division, Kyowa Hakko Kirin Co., Ltd., 3-6-6, Asahi-machi, Machida-shi, Tokyo 194-8533, Japan.
authors.forename: Motoo
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Tsukamoto
authors.affiliation: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Namiko
authors.initials: N
authors.lastname: Yamaguchi
authors.affiliation: Legal and Intellectual Property Department, Kyowa Hakko Kirin Co., Ltd., Ohtemachi Building, 1-6-1 Ohtemachi, Chiyoda-ku, Tokyo 100-8185, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Nakoji
authors.affiliation: Bio Process Research and Development Laboratories, Production Division, Kyowa Hakko Kirin Co., Ltd., 100-1 Hagiwara-machi, Takasaki-shi, Gunma 370-0013, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Endo
authors.affiliation: Translational Research Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd. 1188, Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan and.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kodaira
authors.affiliation: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Medical Sciences, Miyazaki Medical College, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Nishitoh
authors.affiliation: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Naguro
authors.affiliation: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Homma
authors.affiliation: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, ichijo@mol.f.u-tokyo.ac.jp.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
mesh_terms: D000284:Administration, Oral; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000627:therapeutic use*; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; C000611542:K811 compound; C000611544:K812 compound; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse