2. Academic Validation
  3. The ASK1-specific inhibitors K811 and K812 prolong survival in a mouse model of amyotrophic lateral sclerosis

The ASK1-specific inhibitors K811 and K812 prolong survival in a mouse model of amyotrophic lateral sclerosis

  • Hum Mol Genet. 2016 Jan 15;25(2):245-53. doi: 10.1093/hmg/ddv467.
Takao Fujisawa 1,  Motoo Takahashi 2,  Yuka Tsukamoto 1,  Namiko Yamaguchi 1,  Masayoshi Nakoji 3,  Megumi Endo 4,  Hiroshi Kodaira 5,  Yuki Hayashi 1,  Hideki Nishitoh 6,  Isao Naguro 1,  Kengo Homma 1,  Hidenori Ichijo 7
Affiliations

Affiliations

  • 1 Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
  • 2 Tokyo Research Park, R&D Division, Kyowa Hakko Kirin Co., Ltd., 3-6-6, Asahi-machi, Machida-shi, Tokyo 194-8533, Japan.
  • 3 Legal and Intellectual Property Department, Kyowa Hakko Kirin Co., Ltd., Ohtemachi Building, 1-6-1 Ohtemachi, Chiyoda-ku, Tokyo 100-8185, Japan.
  • 4 Bio Process Research and Development Laboratories, Production Division, Kyowa Hakko Kirin Co., Ltd., 100-1 Hagiwara-machi, Takasaki-shi, Gunma 370-0013, Japan.
  • 5 Translational Research Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd. 1188, Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan and.
  • 6 Laboratory of Biochemistry and Molecular Biology, Department of Medical Sciences, Miyazaki Medical College, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
  • 7 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.
PMID: 26604152 DOI: 10.1093/hmg/ddv467
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z